Biophysical Chemistry

Barry S. Cooperman

Photo: 
First Name: 
Barry S.
Last Name: 
Cooperman
Official Title: 
Professor of Chemistry

Biological Chemistry

Contact Information
Office Location: 
358 N, Lab: 307, 309 N
Email: 
cooprman@sas.upenn.edu
Phone: 
(215) 898-6330
Education: 
  • B.A. Columbia College (1962)
  • Ph.D. Harvard University (1968)
  • NATO postdoctoral fellow
  • Institut Pastuer, Paris (1967-68)
  • Merck Faculty Award (1970)
  • Sloan Foundation Fellow (1974-77)
  • N.I.H. Physical Biochemistry Study Section (1978-82)
  • Vice Provost for Research (1982-1995)
  • Chevalier de l’Ordre des Palmes Académique (2004)
  • Fellow of the American Association for the Advancement of Science (2004)
Research Interests: 

 

Our overall thrust is to study the linkage between biological structure and function, using a broad array of chemical, physical, and biological tools. Our major efforts fall in three principal areas.

 

Ribosomes 

We are interested in the structure and function of the bacterial ribosome, which is the site of protein biosynthesis in the cell. Most recently we have been focusing on the application of kinetic and spectroscopic approaches, including the use of single molecule and single-turnover studies in conjunction with fluorescence resonance energy transfer (FRET), to elucidate mechanisms for ribosomal catalysis of protein synthesis. We are particularly interested in the functions of G-proteins on the ribosome, and how these functions are altered by antibiotics and by mutations of tRNAs and ribosomal RNA. We are also pursuing studies on how the rate of protein synthesis is modulated by specific mRNA and oligopeptide sequences.

 

Ribonucleotide reductase (RR) 

RR catalyzes the reduction of nucleoside diphosphates to deoxynucleoside diphosphates and is the key enzyme controlling the rate of DNA synthesis. As such it is highly regulated and is a target enzyme for cancer chemotherapy. Our studies focus on the RRs derived from mammalian cells. We are developing novel and specific inhibitors of this enzyme, using both a rational design approach and combinatorial methods, and based in part on our detailed studies of the allosteric regulation of this enzyme. This work utilizes synthetic organic chemistry, biochemistry, molecular modeling and X-ray crystallography approaches.

 

Serine proteinase inhibitors ("serpins") 

Serpins are known to be of great importance for inflammation process in mammals. We seek to understand the structural basis for the specificity of interaction of these serpins with a variety of serine proteases, using a combination of chemical modification, single turnover FRET kinetics, FT-IR spectroscopy and genetic engineering approaches to elucidate the basic mechanisms underlying such specificity. A second area of interest is serpin polymerization, which underlies several diseases associated with serpin malfunction. These studies are being carried out using single molecule confocal microscopy.

 

Dynamics of Ribosomal Conformational Change

Selected Publications: 

 

Wang Y, Qin H, Kudaravalli RD, Kirillov SV, Dempsey GT, Pan D, Cooperman BS, Goldman YE (2007) Single Molecule Structural Dynamics of EF-G·Ribosome Interaction During Translocation, Biochemistry. in press

 

Grigoriadou C, Marzi S, Pan D, Gualerzi CO, Cooperman BS (2007) The Translational Fidelity Function of IF3 During the Transition from 30S to 70S Initiation Complex. J. Mol. Biol., in press, doi:10.1016/j.jmb.2007.07.031

 

Grigoriadou C, Marzi S, Kirillov S, Gualerzi CO, Cooperman BS (2007) A Quantitative Kinetic Scheme for 70S Translation Initiation Complex Formation. J. Mol. Biol., in press,

doi:10.1016/j.jmb.2007.07.032

 

Chowdhury P, Wang W, Bunagan MR, Klemke JW, Tang J, Lavender S, Saven JG, Cooperman BS, Gai F (2007) Fluorescence Correlation Spectroscopic Study of Serpin Depolymerization by Computationally Designed Peptides. J Mol Biol. 369, 462-73.

 

Pan D, Kirillov S, Cooperman BS (2007) Kinetically Competent Intermediate(s) in the Translocation Step of Protein Synthesis. Molecular Cell,. 25, 519-529.

 

Pan D, Kirillov S, Zhang CM, Hou YM, Cooperman BS (2006) Rapid Ribosomal Translocation Depends on the Conserved 18:55 Base Pair in P-site tRNA. Nature Structural and Molecular Biology, 13, 354-9.

 

Seo HS, Abedin S, Kamp D, Wilson DN, Nierhaus KH, Cooperman BS (2006) EF-G Dependent GTPase on the Ribosome. Conformational Change and Fusidic Acid Inhibition. Biochemistry 45, 2504-14.

 

He J, Roy B, Perigaud C, Kashlan OB, Cooperman BS (2005) The enantioselectivities of the active and allosteric sites of mammalian ribonucleotide reductase. FEBS J. 272,1236-42. 

 

Gao Y, Kashlan OB, Kaur J, Tan C, Cooperman BS (2005) Mechanisms of action of peptide inhibitors of mammalian ribonucleotide reductase targeting quaternary structure. Biopolymers (Peptide Science), 80, 9-17.

 

Purkayastha P, Klemke JW, Lavender S, Oyola R Cooperman BS, Gai F (2005) α1-Antitrypsin polymerization: A fluorescence correlation spectroscopic study. Biochemistry, 44, 2642-2649.

 

Seo HS, Kiel M, Pan D, Raj VS, Kaji A Cooperman BS (2004) Kinetics and Thermodynamics of RRF, EF-G, and Thiostrepton Interaction on the E. coli Ribosome. Biochemistry 43, 12728-40.

 

Tan C, Gao Y, Kaur J, Kashlan, O. B., Cooperman BS (2004) More potent linear peptide inhibitors of mammalian ribonucleotide reductase. Bioorg. Med. Chem. Lett., 14, 5301-5304.

 

Kashlan OB, Cooperman BS (2003) Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry. 42(6): 1696-1706.

 

Gao Y, Liehr S, Cooperman BS (2002) Affinity-Driven Selection of Tripeptide Inhibitors of Ribonucleotide Reductase. Bioorg. Med. Chem. Lett., 12, 513-515.

 

Hsieh MC, Cooperman BS (2002) The Inhibition of Prostate-Specific Antigen (PSA) by a-Antichymotrypsin: Salt-Dependent Activation Mediated by a Conformational Change. Biochemistry 41, 2990-2997.

 

Kashlan OB, Scott CP, Lear JD, Cooperman BS (2002) A Comprehensive Model for the Allosteric Regulation of Mammalian Ribonucleotide Reductase. Functional Consequences of ATP- and dATP-Induced Oligomerization of the Large Subunit. Biochemistry 41, 462-474.

 

Scott CP, Kashlan OB, Lear JD, Cooperman BS (2001) A Quantitative Model for Allosteric Control of Purine Reduction by Murine Ribonucleotide Reductase. Biochemistry 40, 1651-1661.

 

O’Malley KM, Cooperman BS (2001) Formation of the covalent chymotrypsin: antichymotrypsin complex involves no large-scale movement of the enzyme. J. Biol. Chem., 276, 6631-6637.

 

Pender BA, Wu X, Axelsen PH, Cooperman BS (2001) Toward a Rational Design of Peptide Inhibitors of Ribonucleotide Reductase: Structure - Function and Modeling Studies. J. Med. Chem., 44, 36-46.

David W. Christianson

Photo: 
First Name: 
David W.
Last Name: 
Christianson
Official Title: 
Roy and Diana Vagelos Professor in Chemistry and Chemical Biology

Biological Chemistry

Contact Information
Office Location: 
2001 IAST, Lab: 2070 IAST
Email: 
chris@sas.upenn.edu
Phone: 
(215) 898-5714
Admin Support: 
Education: 
  • A.B. Harvard College (1983)
  • A.M. Harvard University (1985)
  • Ph.D. Harvard University (1987)
  • Searle Scholar Award (1989–1992)
  • Young Investigator Award, Office of Naval Research (1989–1992)
  • Alfred P. Sloan Foundation Research Fellow (1992–1994)
  • Camille and Henry Dreyfus Teacher-Scholar Award (1993–1994)
  • Pfizer Award in Enzyme Chemistry, American Chemical Society (1999)
  • Fellow in Natural Sciences (Chemistry), Sidney Sussex College, University of Cambridge (2006)
  • Underwood Fellowship, Department of Biochemistry, University of Cambridge (2006–2007)
  • Senior Fellow, American Asthma Foundation (2006)
  • Fellow of the John Simon Guggenheim Memorial Foundation (2006–2007)
  • National Academies Board on Chemical Sciences and Technology (2011–2017)
  • The Repligen Award in Chemistry of Biological Processes, American Chemical Society (2013)
  • Fellow of the Royal Society of Chemistry (London) (2013)
  • Elizabeth S. and Richard M. Cashin Fellow, Radcliffe Institute for Advanced Study, Harvard University
  • Visiting Professor of Chemistry and Chemical Biology, Harvard University
Research Interests: 

We are interested in structural aspects of the mechanisms of hydrolytic metalloenzymes in the arginase-deacetylase family. To date, we have determined the crystal structures of rat arginase I, human arginase I, human arginase II, and arginases from Plasmodium falciparum, Leishmania mexicana, and Schistosoma mansoni. Structural and enzymological data suggest a mechanism for arginine hydrolysis in which both manganese ions activate a bridging hydroxide ion for nucleophilic attack at the guanidinium group of arginine in the first step of catalysis. Based on our structural and mechanistic analyses, we designed and synthesized boronic acid analogues of arginine such as 2-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) [Baggio et al. (1997) J. Am. Chem. Soc. 119, 8107]. The boronic acid moiety of ABH similarly undergoes nucleophilic attack by the metal-bridging hydroxide ion to yield a metal-bound boronate anion that mimics the tetrahedral intermediate and its flanking transition states in catalysis (Figure 1), as shown in X-ray crystallographic studies of rat arginase I [Cox et al. (1999) Nature Struct. Biol. 6, 1043], human arginase I [Di Costanzo et al. (2005) Proc. Natl. Acad. Sci. USA, 102, 13058], P. falciparum arginase [Dowling et al. (2010) Biochemistry 49 5600], and L. mexicana arginase [D' Antonio et al. (2013) Arch. Biochem. Biophys. 535, 163]

Figure 1: Human arginase I-ABH complex. (a) Omit electron density map of ABH bound in the enzyme active site at 1.29 Å resolution. Water molecules appears as red spheres and Mn(II) ions appears as larger pink spheres. (b) Summary of arginase-ABH interactions; manganese coordination interactions are designated by green dashed lines, and hydrogen bonds are indicated by black dashed lines. (c) Stabilization of the tetrahedral intermediate (and flanking transition states) in the arginase mechanism based on the binding mode of ABH.

 

We have also used ABH as a chemical tool for probing the role of arginase in regulating arginine bioavailability for nitric oxide (NO) biosynthesis in tissues and in live animals. We discovered that arginase inhibition by ABH enhances smooth muscle relaxation in ex vivo organ bath studies. Since smooth muscle relaxation in the corpus cavernosum of the penis is necessary for erection, we concluded that human penile arginase is a potential target for the development of new therapies in the treatment of erectile dysfunction [Cox et al. (1999) Nature Struct. Biol. 6, 1043]. Our subsequent in vivo studies demonstrated that arginase inhibition by ABH enhances erectile function and vasocongestion in the male and female genitalia, so we concluded that both male erectile dysfunction and female sexual arousal disorder are potentially treatable by ABH [Cama et al. (2003) Biochemistry 42, 8445; Christianson (2005) Acc. Chem. Res. 38, 191]. More recent studies show that ABH may also be useful in the treatment of certain cardiovascular disorders such as atherosclerosis [Santhanam et al. (2007) Circulation Res. 101, 692; Ryoo et al. (2008) Circulation Res. 102, 923]. The biopharmaceutical company Arginetix was founded in 2008 based on our arginase inhibitor technology.

 

Our work with metal-dependant histone deacetylases recently yielded the first crystal structure of a histone deacetylase complexed with a macrocyclic depsipeptide inhibitor (Figure 2) [Cole et al. (2011) J. Am. Chem. Soc. 133, 12474]. Additionally, we recently showed that mutations in histone deacetylase 8 identified in patients diagnosed with Cornelia de Lange Syndrome compromise catalytic activity by causing structural changes in the active site that perturb substrate binding and catalysis [Deardorff et al. (2012) Nature 489, 313; Decroos et al. (2014) ACS Chem. Biol., in press.]. In addition to our work with arginase, we are studying other metalloenzymes that adopt the arginase fold, such as polyamine deacetylase [Lombardi et al. (2011) Biochemistry 50, 1808].

 

In other metalloenzyme work, we have determined the crystal structure of A. aeolicus LpxC, a zinc-requiring enzyme that catalyzes the first step of lipid A biosynthesis in Gram-negative bacteria [Whittington et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8146] (Figure 3). Subsequent structural studies have allowed us to pinpoint regions of the active site that interact with the fatty acid and diphosphate moieties of the substrate [Gennadios et al. (2006) Biochemistry 45, 7940; 15216], and these studies have guided the first steps in the structure-based design of new LpxC inhibitors that may ultimately be useful in the treatment of Gram-negative bacterial infections [Shin et al. (2007) Bioorg. Med. Chem. 15, 2617]. To date, we have broadened these structural studies to include LpxC enzymes from Gram-negative pathogens Y. pestis (bubonic plague) and F. tularensis (tularemia) [Cole et al. (2011) Biochemistry 50, 258.]

 

Figure 3: Structure and biological function of LpxC. This zinc enzyme catalyzes the first committed step of lipid A biosynthesis; lipid A is the hydrophobic anchor of lipopolysaccharide, which comprises the outer leaflet of the outer membrane of Gram-negative bacteria. The crystal structure of LpxC reveals a hydrophobic tunnel in the active site that accommodates the fatty acid moiety of the substrate, and this binding interaction is required for the active site to adopt a catalytically-active conformation.

 

Structural Basis of Terpenoid Biosynthesis

 

The family of terpenoid natural products currently numbers more than 70,000 members found in all forms of life. Terpenoids, are involved in diverse biological functions such as the mediation of plant-parasite interactions or the modulation of membrane fluidity. Since times of antiquity, terpenoid natural products have also been essential components of the pharmacopeia as analgesics, antibiotics, and anti-cancer compounds (e.g., Taxol). We are interested in the enzymes that catalyze the biosynthesis of different cyclic terpenoids [Christianson (2006) Chem. Rev. 106, 3412; Christianson (2008) Curr. Opin. Chem. Biol. 12, 141]. We have determined the three-dimensional crystal structures of terpenoid cyclases from various bacterial, fungal, and plant sources, such as epi-isozizaene synthase from S. colicolor [Aaron et al. (2010) Biochemistry 49, 1787], bornyl diphosphate synthase from culinary sage [Whittington et al. (2002), Proc. Natl. Acad. Sci. USA 99, 15375], aristolochene synthase from A. terreus [Shishova et al. (2007) Biochemistry 46, 1941], trichodiene synthase from F. sporotrichioides [Rynkiewicz et al. (2001) Proc. Natl. Acad. Sci. USA 98, 13543], δ-cadinene synthase from cotton [Gennadios et al. (2009) Biochemistry 48, 6175] and taxadiene synthase from the Pacific yew (which catalyzes the first committed step in the biosynthesis of Taxol, a potent cancer chemotherapeutic compound), [Köksal et al. (2011) Nature 469, 116]. To illustrate, structures of bornyl diphosphate synthase and taxadiene synthase are shown in Figures 4 and 5, respectively. These structures guide the study of site-specific mutants and alternative substrates as we explore the structural basis of diversity in terpenoid biosynthesis [e.g., see: Vedula et al. (2005) Biochemistry 44, 12719; Vedula et al. (2008) Arch. Biochem. Biophys. 469, 184; Christianson (2007) Science 316, 60], Köksal et al. (2012) Biochemistry 51, 3003, 301.

 

Figure 4: Reaction catalyzed by bornyl diphosphate synthase. Aza analogues of carbocation intermediates are shown in boxes; crystal structures of their complexes with the synthase reveal structural inferences on catalysis. The enzyme undergoes significant conformational changes upon the binding of 3 Mg2+ ions and pyrophosphate (or a substrate diphosphate group). These conformational changes sequester the active site from bulk solvent and trigger substrate ionization to initiate catalysis [Whittington et al. (2002) Proc. Natl. Acad. Sci. USA 99, 15375].

Figure 5: Structural relationships among terpenoid cyclases.The class I terpenoid cyclase fold of pentalenene synthase (blue) contains metal-binding motifs DDXXD and (N,D)DXX(S,T)XXXE (red and orange, respectively); in 5-epi-aristolochene synthase, this domain is linked to a smaller, vestigial domain (green). A related domain is found in the class II terpenoid cyclase fold of squalene-hopene cyclase, where it contains the general acid motif DXDD (brown) and a second domain (yellow) inserted between the first and second helices; a hydrophobic plateau flanking helix 8 (gray stripes) enables membrane insertion. Taxadiene synthase contains both class I and class II terpenoid cyclase folds, but only the class I domain is catalytically active. The role of N-termini (purple) in class I plant cyclases is to "cap" the active site, as shown for 5-epi-aristolochene synthase.

Selected Publications: 

Köksal, M., Jin, Y., Coates, R.M., Croteau, R., Christianson, D.W. (2011) Taxadiene Synthase Structure and Evolution of Modular Architecture in Terpene Biosynthesis. Nature 469, 116-120. 

 

Cole, K.E., Gattis, S.G., Angell, H.D., Fierke, C.A., Christianson, D.W. (2011) Structure of the Metal-Dependent Deacetylase LpxC from Yersinia enterocolitica Complexed with the Potent Inhibitor CHIR-090. Biochemistry 50, 258-265.

 

Lombardi, P.M., Angell, H.D., Whittington, D.A., Flynn, E.F., Rajashankar, K.R., Christianson, D.W. (2011) Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases. Biochemistry 50, 1808-1817.

 

Köksal, M., Hu, H., Coates, R.M., Peters, R.J., Christianson, D.W. (2011) Structure and Mechanism of the Diterpene Cyclase ent-Copalyl Diphosphate Synthase. Nature Chem. Biol. 7, 431-433.

 

Cole, K.E., Dowling, D.P., Boone, M.A., Phillips, A.J., Christianson, D.W. (2011) Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases. J. Am. Chem. Soc. 133, 12474-12477 (Communication to the Editor).

 

Ilies, M., Di Costanzo, L., Dowling, D.P., Thorn, K.J., Christianson, D.W. (2011) Binding of α, α-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design. J. Med. Chem. 54, 5432-5443.

 

Lombardi, P.M., Cole, K.A., Dowling, D.P., Christianson, D.W. (2011) Structure, Mechanism, and Inhibition of Histone Deacetylases and Related Metalloenzymes. Curr. Op. Struct. Biol. 21, 735-743 (invited review). 

 

Köksal, M., Chou, W.K.W., Cane, D.E., Christianson, D.W. (2012) Structure of 2-Methylisoborneol Synthase from Streptomyces coelicolor and Implications for the Cyclization of a Noncanonical C-Methylated Monoterpenoid Substrate. Biochemistry 51, 3011-3020.

 

Deardorff, M.A., Bando, M., Nakato, R., Watrin, E., Itoh, T., Minamino, M., Saitoh, K., Komata, M., Katou, Y., Clark, D., Cole, K.E., De Baere, E., Decroos, C., Di Donato, N., Ernst, S., Francey, L.J., Gyftodimou, Y., Hirashima, K., Hullings, M., Ishikawa, Y., Jaulin, C., Kaur, M., Kiyono, T., Lombardi, P.M., Magnaghi-Jaulin, L., Mortier, G.R., Nozaki, N., Petersen, M.B., Seimiya, H., Siu, V.M., Suzuki, Y., Takagaki, K., Wilde, J.J., Willems, P.J., Prigent, C., Gillessen-Kaesbach, G., Christianson, D.W., Kaiser, F.J., Jackson, L.G., Hirota, T., Krantz, I.D., Shirahige, K. (2012) HDAC8 Mutations in Cornelia de Lange Syndrome Affect the Cohesin Acetylation Cycle. Nature 489, 313-317.

 

D'Antonio, E.L., Hai, Y., Christianson, D.W. (2012) Structure and Function of Non-Native Metal Clusters in Human Arginase I. Biochemistry 51, 8399-8409.

 

D'Antonio, E.L., Ullman, B., Roberts, S.C., Gaur Dixit, U., Wilson, M.E., Hai, Y., Christianson, D.W. (2013) Crystal Structure of Arginase from Leishmania mexicana and Implications for the Inhibition of Polyamine Biosynthesis in Parasitic Infections. Arch. Biochem. Biophys. 535, 163-176.

 

Genshaft, A., Moser, J.-A.S., D'Antonio, E.L., Bowman, C.M., Christianson, D.W. (2013) Energetically Unfavorable Amide Conformations for N6-Acetyllysine Side Chains in Refined Protein Structures. Proteins: Struct., Funct., Bioinf. 81, 1051–1057

 

Köksal, M., Chou, W.K.W., Cane, D.E., Christianson, D.W. (2013) Unexpected Reactivity of 2-Fluorolinalyl Diphosphate in the Active Site of Crystalline 2-Methylisoborneol Synthase. Biochemistry 52, 5247-5255.

 

Chen, M., Al-lami, N., Janvier, M., D'Antonio, E.L., Faraldos, J.A., Cane, D.E., Allemann, R.K., Christianson, D.W. (2013) Mechanistic Insights from the Binding of Substrate and Carbocation Intermediate Analogues to Aristolochene Synthase. Biochemistry 52, 5441-5453.

 

Hai, Y., Dugery, R.J., Healy, D., Christianson, D.W. (2013) Formiminoglutamase from Trypanosoma cruzi is an Arginase-Like Manganese Metalloenzyme. Biochemistry 52, 9294-9309.

 

Li, R., Chou, W.K.W., Himmelberger, J.A., Litwin, K.M., Harris, G.G., Cane, D.E., Christianson, D.W. (2014) Reprogramming the Chemodiversity of Terpenoid Cyclization by Remolding the Active Site Contour of epi-Isozizaene Synthase. Biochemistry 53, 1155-1168.

 

Kaiser, F.J., Ansari, M., Braunholz, D., Gil-Rodríguez, M.C., Decroos, C., Wilde, J.J., Fincher, C.T., Kaur, M., Bando, M., Bowman, C.M., Bradley, J., Clark, D., del Campo-Casanelles, M., Di Donato, N., Dubbs, H., Eckhold, J., Ernst, S., Ferreira, J.C., Francey, L., Gehlken, U., Guillén-Navarro, E., Gyftodimou, Y., Hall, B.D., Hennekam, R., Hullings, M., Hunter, J., Kline, A.D., Krumina, Z., Leppig, K., Lynch, S.A., Mallozzi, M.B., Mannini, L., McKee, S., Mehta, S., Micule, L., Mohammed, S., Moran, E., Mortier, G.R., Moser, J.-A.S., Nozaki, N., Nunes, L., Pappas, J., Pérez-Aytés, A., Petersen, M.B., Poffyn, A., Puisac, B., Revencu, N., Roeder, E., Saitta, S., Scheuerle, A., Siu, V.M., Thiese, H., Vater, I., Willems, P., Williamson, K., Wilson, L., Hakonarson, H., Wierzba, J., Musio, A., Gillessen-Kaesbach, G., Ramos, F.J., Jackson, L.G., Shirahige, K., Pié, J., Christianson, D.W., Krantz, I.D., FitzPatrick, D.R., Deardorff, M.A. (2014) HDAC8 Mutations Cause an X-Linked Clinically Recognizable Cornelia de Lange Syndrome-Like Disorder. Hum. Mol. Genet. 23, 2888-2900 (cover article).

 

Hai, Y., Edwards, J.E., Van Zandt, M.C., Hoffmann, K.F., Christianson, D.W. (2014) Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis. Biochemistry 53, 4671-4684.

 

Decroos, C., Bowman, C.M., Moser, J.-A.S., Christianson, K.E., Deardorff, M.A., Christianson, D.W. (2014) Compromised Structure and Function of HDAC8 Mutants in Cornelia de Lange Syndrome Spectrum Disorders. ACS Chem. Biol. 9, 2157-2164.

 

Hai, Y., Kerkhoven, E.J., Barrett, M.P., Christianson, D.W. (2015) Crystal Structure of an Arginase-Like Protein from Trypanosoma brucei that Evolved without a Binuclear Manganese Cluster. Biochemistry 54, 458-471.

 

Decroos, C., Clausen, D.J., Haines, B.E., Wiest, O., Williams, R.M., Christianson, D.W. (2015) Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8. Biochemistry 54, 2126-2135.

David M. Chenoweth

Photo: 
First Name: 
David M.
Last Name: 
Chenoweth
Official Title: 
Associate Professor of Chemistry

Organic and Bioorganic Chemistry

Contact Information
Office Location: 
2002 IAST, lab: 2020,2080,2100 IAST
Email: 
dcheno@sas.upenn.edu
Phone: 
215-­573-­1953
Admin Support: 
Education: 
  • B.S. Indiana University-Purdue University Indianapolis (1999)
  • Organic Chemist, Eli Lilly & Co., Indianapolis, IN (2000 – 2004)
  • Ph.D. California Institute of Technology (2009)
  • Kanel Foundation Predoctoral Fellow (2007 – 2009)
  • Caltech Herbert Newby McCoy Award (2009)
  • NIH/NIGMS Postdoctoral Fellow, Massachusetts Institute of Technology (2009 – 2010)
Research Interests: 

Research in the Chenoweth laboratory is grounded in organic chemistry and molecular recognition with applications to biological and materials problems. We synthesize molecules and study their properties and interactions for a broad range of applications in bioorganic and materials chemistry. We are particularly interested in the design and synthesis of new molecules that can modulate nucleic acid and protein structure. Additionally, we are equally interested in the synthesis of new materials with sensing and self-assembly properties.

 

Undergraduate students, graduate students, and postdoctoral researchers are exposed to a diverse array of topics including organic chemistry, synthesis, bioorganic chemistry, macromolecular structure (nucleic acids and proteins), biochemistry, and polymer chemistry.

Selected Publications: 

Zhang, Yitao; Malamakal, Roy M.; Chenoweth, David M. “Aza-Glycine Induces Collagen Hyperstability” J. Am. Chem. Soc. 2015, ASAP. DOI: 10.1021/jacs.5b04590. See Chemical & Engineering News story by Stu Borman: “Chemical Modification Is Best Ever At Strengthening And Stabilizing Collagen” Chemical & Engineering News, Volume 93, Issue 38, p. 7, News of The Week.

 

Zhang, Yitao; Malamakal, Roy M.; Chenoweth, David M. “A Single Stereodynamic Center Modulates the Rate of Self-Assembly in a Biomolecular System” Angew. Chem. Int. Ed. 2015, 54, 10826-10832.

 

Suh, Sung-Eun; Barros, Stephanie A.; Chenoweth, David M. “Triple Aryne–Tetrazine Reaction Enabling Rapid Access to a New Class of Polyaromatic Heterocycles” Chemical Science 2015, 6, 5128-5132.

 

Tran, Mai N.; Chenoweth, David M. “Synthesis and Properties of Lysosome-Specific Photoactivatable Probes for Live-Cell Imaging” Chemical Science 2015, 6, 4508-4512.

 

Barros, Stephanie A.; Chenoweth, David M. “Triptycene-Based Small Molecules Modulate (CAG)·(CTG) Repeat Junctions" Chemical Science 2015, 6, 4752-4755.

 

Tran, Mai N.; Chenoweth, David M. “Photoelectrocyclization as an Activation Mechanism for Organelle Specific Live-Cell Imaging Probes” Angew. Chem. Int. Ed. 2015, 54, 6442-6446.

 

Ballister, Edward R.; Ayloo, Swathi; Chenoweth, David M.; Lampson, Michael A.; Holzbaur, Erika L.F. “Optogenetic Control of Organelle Transport Using a Photocaged Chemical Inducer of Dimerization” Current Biology 2015, 10, R407-R408.

 

Ballister, Edward R.; Aonbangkhen, Chanat; Mayo, Alyssa M.; Lampson, Michael A.; Chenoweth, David M. "Localized Light-Induced Protein Dimerization in Living Cells using a Photocaged Dimerizer” Nature Communications 2014, 5, 5475.

 

Barros, Stephanie A.; Chenoweth, David M. "Recognition of Nucleic Acid Junctions Using Triptycene-Based Molecules” Angew. Chem. Int. Ed. 2014, 53, 13746-13750.

 

Rarig, Robert-André F.; Tran, Mai N.; Chenoweth, David M. "Synthesis and Conformational Dynamics of the Reported Structure of Xylopyridine A” J. Am. Chem. Soc. 2013, 135, 9213–9219, ASAP.

 

Chenoweth, David M.; Meier, Jordan L.; Dervan, Peter B. "Pyrrole-Imidazole Polyamides Distinguish Between Double-Helical DNA and RNA” Angew. Chem. Int. Ed. 2013, 52, 415-418.

 

Weizmann, Yossi; Chenoweth, David M.; Swager, Timothy, M. "DNA−CNT Nanowire Networks for DNA Detection” J. Am. Chem. Soc. 2011, 133, 3238–3241.

 

Chenoweth, David M.; Dervan, Peter B. “Structural Basis for Cyclic Py-Im Polyamide Allosteric Inhibition of Nuclear Receptor Binding” J. Am. Chem. Soc. 2010, 132, 14521. Selected for the cover of JACS Oct. 20, 2010, Vol 132, Issue 41. Covered by Chemical and Engineering News Sept. 27, 2010 issue, “Putting DNA in a Bind”.

 

Weizmann, Yossi; Chenoweth, David M.; Swager, Timothy, M. “Addressable Terminally-Linked DNA-CNT Nanowires” J. Am. Chem. Soc. 2010, 132, 14009.

 

Weizmann, Yossi; Lim, Jeewoo; Chenoweth, David M.; Swager, Timothy, M. “Regiospecific Synthesis of Au-Nanorod/SWCNT/Au-Nanorod Heterojunctions” Nano Lett. 2010, 10, 2466.

 

Chenoweth, Kimberly; Chenoweth, David M.; Goddard III, William A. “Cyclooctyne-based Reagents for Uncatalyzed Click Chemistry: A Computational Survey” Org. Biomol. Chem. 2009, 7, 5255.

 

Chenoweth, David M.; Harki, Daniel A.; Dervan, Peter B. “Oligomerization Route to DNA Binding Py-Im Polyamide Macrocycles” Org. Lett. 2009, 11, 3590.

 

Chenoweth, David M.; Dervan, Peter B. “Allosteric Modulation of DNA by Small Molecules” Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13175. Covered by Nature News: "Get into the groove" Nature 2009, 460, 669. Also selected by the Stanford Synchrotron (SSRL) as a science highlight for November 2009.

 

Chenoweth, David M.; Harki, Daniel A.; Dervan, Peter B. “Solution-Phase Synthesis of Pyrrole-Imidazole Polyamides” J. Am. Chem. Soc. 2009, 131, 7175.

 

Chenoweth, David M.; Harki, Daniel A.; Phillips, John W.; Dose, Christian; Dervan, Peter B. “Cyclic Pyrrole-Imidazole Polyamides Targeted to the Androgen Response Element” J. Am. Chem. Soc. 2009, 131, 7182.

 

Chenoweth, David M.; Chenoweth, Kimberly; Goddard III, William A. “Lancifodilactone G: Insights about an Unusually Stable Enol” J. Org. Chem., 2008, 73, 6853.

 

Dose, Christian; Farkas, Michelle E.; Chenoweth, David M.; Dervan, Peter B. “Next Generation Hairpin Polyamides with (R)-3,4-Diaminobutyric Acid Turn Unit” J. Am. Chem. Soc., 2008, 130, 6859.

 

Chenoweth, David M.; Viger, Anne; Dervan, Peter B. “Fluorescent Sequence-Specific dsDNA Binding Oligomers” J. Am. Chem. Soc., 2007, 129, 2216. Covered by Chemical and Engineering News.

 

Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B. “Programmable oligomers targeting 5'-GGGG-3' in the minor groove of DNA and NF-k B binding inhibition” Bioorg. Med. Chem., 2007, 15, 759.

 

Doss, Raymond M.; Marques, Michael M.; Foister, Shane; Chenoweth, David M.; Dervan, Peter B. “Programmable Oligomers for Minor Groove DNA Recognition” J. Am. Chem. Soc., 2006, 128, 9074.

 

Nurok, D.; Frost, M. C.; Chenoweth, D. M. “Separation using planar chromatography with electroosmotic flow” J. Chromatogr., A, 2000, 903, 211. 

 

Nurok, David; Frost, Megan C.; Pritchard, Cary L.; Chenoweth, David M. “The performance of planar chromatography using electroosmotic flow” J. Planar Chromatogr.-Mod. TLC, 1998, 11, 244.

Tobias Baumgart

Photo: 
First Name: 
Tobias
Last Name: 
Baumgart
Official Title: 
Professor of Chemistry

Physical and Biological Chemistry

Additional Titles: 
Graduate Chair
Contact Information
Office Location: 
250 Chemistry Bldg.
Email: 
baumgart@sas.upenn.edu
Phone: 
215.573.7539
Fax: 
215.898.6242
Admin Support: 
Education: 

• Postdoctoral associate with Prof. Watt Webb at Cornell University (2001 – 2005)

 

• PhD from Max Planck Institute for Polymer Research and Johannes Gutenberg University of Mainz (2001)

 

• Diploma in Chemistry from the University of Clausthal, Germany (1998)

Research Interests: 

Research in the Baumgart group is largely centered on the physical chemistry of amphiphile membranes with lateral heterogeneity resulting from non-ideal mixing. Our aims include characterization of biologically relevant membranes including lipids and proteins, where we investigate both composition and shape (curvature) heterogeneity. Both of these aspects are thought to be highly relevant to the function of biological membranes. We focus on freely suspended, rather than solid supported membranes, with an emphasis on bilayer membranes, but we also include monolayer systems. We investigate membranes that laterally segregate into co-existing fluid phases, and are particularly interested in quantitatively understanding the phenomenon of line tension at the phase boundary. We also examine molecular details that govern the partitioning of functionally relevant protein constructs between coexisting membrane phases and thereby aim to contribute to enhancing the biophysical understanding of transmembrane signal transduction, particularly in immune cells such as T-cells, B-cells and mast cells. Our research on aspects of membrane shape is directed at understanding how molecules sort in membrane curvature gradients. This curvature sorting likely contributes substantially to intracellular membrane sorting and trafficking. Furthermore we have recently begun to investigate phase coexistence in binary mixtures of amphiphilic di-block copolymers. Finally, we develop methods to pattern cellular signaling ligands, such as antibodies and adhesion molecules, on pattern scales both above and below optical resolution.

Selected Publications: 

31) Heinrich, M., Tian A.,Esposito C., Baumgart T. (2010). Dynamic sorting of lipids and proteins by membrane curvature: a moving phase boundary problem. Proceedings of the National Academy of Sciences. In Print.

30) Johnson, S., Stinson, B., Reminik, J., Go, M., Fang, X., & Baumgart, T. (2010). Temperature dependent phase behavior and protein partitioning in giant plasma membrane vesicles. Biochimica et Biophysica Acta - Biomembranes. In Print.

29) Capraro, B. R., Yoon, Y., Cho, W., Baumgart, T. (2010). Curvature sensing by the epsin N-terminal homology (ENTH) domain measured on cylindrical lipid membrane tethers. Journal of the American Chemical Society, 132 (4), 1200-1201.

28) Levental, I., Byfield, F. J., Choudhourie, P., Madara, J., Gai, F., Baumgart, T., & Janmey P. A. (2009). Cholesterol-dependent phase separation in cell-derived giant plasma membrane vesicles. Biochemical Journal, 424 (2), 163-167.

27) Baker, R. G., Hsu, C. J., Lee, D., Jordan, M. S., Maltzman, J. S., Hammer, D. A., Baumgart, T., & Koretzky, G. A. (2009). The adapter protein SLP-76 mediates “outside-in” integrin signaling and function in T cells. Molecular and Cellular Biology, 29 (20), 5578-5589.

26) Christian, D., Tian, A., Ellenbroek, W., Levental, I., Rajagopal, K., Janmey, P., Liu, A., Baumgart, T., & Discher, D. (2009). Spotted vesicles, striped micelles and Janus assemblies induced by ligand binding. Nature Materials, 8, 843-849. DOI

25) Oh, H., Mohler III, E. R., Tian, A., Baumgart, T., & Diamond, S. L. (2009). Membrane cholesterol is a biomechanical regulator of neutrophil adhesion. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1290-1297.

24) Tian, A., Capraro, B. R., Esposito, C., & Baumgart, T. (2009). Bending stiffness depends on curvature of ternary lipid mixture tubular membranes. Biophysical Journal, 97 (6), 1636-1646.

23) Das SL, Jenkins JT, Baumgart T. "Neck geometry and shape transitions in vesicles with co-existing fluid phases: Role of Gaussian curvature stiffness versus spontaneous curvature." Europhysics Letters, 2009, 86, 48003-48008.

22) Tian, A. and Baumgart, T. "Sorting of lipids and proteins in membrane curvature gradients." Biophysical Journal, 2009, 96, 2676-2688.

21) Das S., Tian A., Baumgart T., "Mechanical stability of micropipette aspirated giant vesicles with fluid phase coexistence." Journal of Physical Chemistry, B 2008, 112, 11625-11630.

20) Heinrich M.C., Levental I., Gelman H., Janmey P.A., Baumgart T. "Critical exponents for line tension and dipole density difference from lipid monolayer domain boundary fluctuations." Journal of Physical Chemistry, B 2008, 112, 8063-8068.

Department of Chemistry

231 S. 34 Street, Philadelphia, PA 19104-6323

215.898.8317 voice | 215.573.2112 fax | web@chem.upenn.edu

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