The Shape of Things: Structure and Function in Chemical Biology
Posted March 26, 2007
Presented By
Overview
On November 9, 2006, the Chemical Biology Discussion Group held a session focused on research on the relationship between physical structures and their biological function. The goal of such research is to tinker with such structures to improve biological outcomes.
Blake Peterson described his work designing and synthesizing nonnatural receptors that interact with the cell's endocytic machinery. These receptors can grab onto molecules that would not normally enter the cell very easily, such as antibodies and certain drugs, and bring them into the cell for research or therapeutic purposes. Marc Greenberg presented his work on the effects of ionizing radiation on DNA. He is using chemical tools to recapitulate the damage caused by radiation in ways that are easier to manipulate and study. Peter Tonge discussed his work on biochemical pathways in Mycobacterium tuberculosis, the causative agent of tuberculosis. He and his research group are investigating key metabolic pathways, looking to interfere with them and kill the bacteria. They are using X-ray crystal structures and detailed reaction mechanisms to design new inhibitors of key enzymes that are required for mycobacterial growth and infection.
Use the tabs above to find a meeting report and multimedia from this event.
Web Sites
American College of Radiology
Professional organization representing radiologists, radiation oncologists, interventional radiologists, and medical physicists.
Division of Tuberculosis Elimination
The National Center for HIV, STD, and TB Prevention at the Centers for Disease Control provides news and updates, highlights, and other resources for tuberculosis information.
Human Plasma Membrane Receptome
Descriptive database of major classes of human plasma membrane receptors.
Medical Physics
Information on medical physics from the Department of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins University.
Receptor Mediated Endocytosis
Tutorial from the University of Texas Medical Branch.
Tuberculosis
Fact sheet from the World Health Organization.
Articles
Synthetic Mimics of Mammalian Cell Surface Receptors: Prosthetic Molecules that Augment Living Cells
Boonyarattanakalin S, Martin SE, S. Dykstra A, Peterson BR. 2004. Synthetic mimics of small mammalian cell surface receptors. J. Am. Chem. Soc. 126: 16379-16386.
Boonyarattanakalin S, Hu J, Dykstra-Rummel S, August A, Peterson BR. 2007. Endocytic delivery of vancomycin mediated by a synthetic cell surface receptor: rescue of bacterially infected mammalian cells and tissue targeting in vivo. J. Am. Chem. Soc. 129: 268-269.
Boonyarattanakalin S, Athavankar S, Sun Q, Peterson BR. 2006. Synthesis of an artificial cell surface receptor that enables oligohistidine affinity tags to function as metal-dependent cell-penetrating peptides. J. Am. Chem. Soc. 128: 386-387.
Boonyarattanakalin S, Martin SE, Sun Q, Peterson BR. 2006. A synthetic mimic of human Fc receptors: Defined chemical modification of cell surfaces enables efficient endocytic uptake of human immunoglobulin-G. J. Am. Chem. Soc. 128: 11463-11470.
Hussey SL, He E, Peterson BR. 2001. A synthetic membrane-anchored antigen efficiently promotes uptake of antifluorescein antibodies and associated protein A by mammalian cells. J. Am. Chem. Soc. 123: 12712-12713.
Hussey SL, Peterson BR. 2002. Efficient delivery of streptavidin to mammalian cells: Clathrin-mediated endocytosis regulated by a synthetic ligand. J. Am. Chem. Soc. 124: 6265-6273.
Martin SE, Peterson BR. 2003. Non-natural cell surface receptors: synthetic peptides capped with N-cholesterylglycine efficiently deliver proteins into mammalian cells. Bioconjugate Chem. 14: 67-74.
Peterson BR. 2005. Synthetic mimics of mammalian cell surface receptors: Prosthetic molecules that augment living cells. Org. Biomol. Chem. 3: 3607-3612.
DNA Interstrand Cross-linking by a Modified Nucleotide
Hong IS, Ding H, Greenberg MM. 2006. Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions. J Am. Chem. Soc. 128: 2230-1. Full Text
Hong IS, Ding H, Greenberg MM. 2006. Oxygen independent DNA interstrand cross-link formation by a nucleotide radical. J. Am. Chem. Soc. 1282: 485-91. Full Text
Hong IS, Greenberg MM. 2005. DNA interstrand cross-link formation initiated by reaction between singlet oxygen and a modified nucleotide. J. Am. Chem. Soc. 127:10510-10511. Full Text
Hong IS, Greenberg MM. 2005. Efficient DNA interstrand cross-link formation from a nucleotide radical. J. Am. Chem. Soc. 127: 3692-3693.
Hong IS, Greenberg MM. 2004. Mild generation of 5-(2′-deoxyuridinyl)methyl radical from a phenyl selenide precursor. Org. Lett. 6: 5011-5013.
Kim J, Kreller CR, Greenberg MM. 2005. Preparation and analysis of oligonucleotides containing the c4′-oxidized abasic site and related mechanistic probes. J. Org. Chem. 70:8122-8129. Full Text
Kodama T, Greenberg MM. 2005. Preparation and analysis of oligonucleotides containing lesions resulting from C5′-oxidation. J. Org. Chem. 70(24):9916-24. Full Text
Mycolic Acids, Menaquinone and Mycobactin: Mining the Magic Mountain for Novel Tuberculosis Drug Targets
Carlisle-Moore L, Gordon CR, Machutta CA, et al. 2005. Substrate recognition by the human fatty-acid synthase. J. Biol. Chem. 280: 42612-42618. Full Text
Kolappan S, Zwahlen J, Zhou R, et al. 2007. Lysine 190 is the catalytic base in MenF, the menaquinone-specific isochorismate synthase from E. Coli: implications for an enzyme family. Biochemistry 46: 946-953.
Parikh SL, Xiao G, Tonge PJ. 2000. Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry 39: 7645-7650.
Rafi SB, Cui G, Song K, et al. 2006. Insight through molecular mechanics Poisson-Boltzmann surface area calculations into the binding affinity of triclosan and three analogues for FabI, the E. coli enoyl reductase. J. Med. Chem. 49: 4574-4580.
Rafi S, Novichenok P, Kolappan S, et al. 2006. Structure of acyl carrier protein bound to Fabi, the FASII enoyl reductase from Escherichia coli. J. Biol. Chem. [Epub ahead of print] Full Text
Rawat R, Whitty A, Tonge PJ. 2003. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc. Natl. Acad. Sci. 100: 13881-13886.
Sivaraman S, Sullivan TJ, Johnson KF, et al. 2004. Inhibition of the bacterial enoyl reductase FabI by triclosan: a structure-reactivity analysis of FabI inhibition by triclosan analogues. J. Med Chem. 47: 509-18.
Sivaraman S, Zwahlen J, Bell AF, et al. 2003. Structure-activity studies of the inhibition of FabI, the enoyl reductase from Escherichia coli, by triclosan: kinetic analysis of mutant FabIs. Biochemistry 42: 4406-4413.
Stewart MJ, Parikh S, Xiao G, et al. 1999. Structural basis and mechanism of enoyl reductase inhibition by triclosan. J. Mol. Biol. 290: 859-865.
Sullivan TJ, Truglio JJ, Boyne ME, et al 2006. High affinity InhA inhibitors with activity against drug resistant strains of Mycobacterium tuberculosis. ACS Chemical Biology 1: 43-53.
Zwahlen J, Kolappan S, Zhou R, et al. 2007. Structure and mechanism of MbtI, the salicylate synthase from Mycobacterium tuberculosis. Biochemistry 46: 954-964.
Speakers
Blake Peterson, PhD
Pennsylvania State University
e-mail | web site | publications
Blake Peterson is an associate professor of chemistry at the Pennsylvania State University, where he and his research group investigate synthetic mimics of mammalian cell surface receptors, synthetic ligands of steroid hormone receptors, and mutagenic ribonucleosides as antiviral agents. Peterson received his BS from the University of Nevada, Reno, in 1990 and his PhD from the University of California, Los Angeles in 1994. He performed postdoctoral studies as a Damon Runyon-Walter Winchell postdoctoral fellow at Harvard University. His other awards and honors include American Cancer Society Research Scholar, received in 2003, and Camille Dreyfus Teacher Scholar in 2004.
Marc M. Greenberg, PhD
Johns Hopkins University
e-mail | web site | publications
Marc Greenberg is a professor of chemistry, and director of the Chemistry Biology Interface Graduate Training Program at Johns Hopkins University. He is also a member of the Program in Molecular and Computational Biophysics (PMCB) and the graduate program in Molecular Pharmacology. He holds undergraduate degrees from New York University (BS Chemistry with Honors, 1982) and The Cooper Union School of Engineering (BE Chemical Engineering, 1982), and received his PhD from Yale University in 1988. Postdoctoral studies took him to the California Institute of Technology, where he served as an American Cancer Society postdoctoral fellow. He began his independent research career in the Department of Chemistry at Colorado State University, where he held a full professorship until moving to Johns Hopkins in 2002.
Peter J. Tonge, PhD
State University of New York, Stony Brook
e-mail | web site | publications
Peter Tonge is a professor of chemistry at State University of New York, Stony Brook, where he works on the rational design of tuberculosis drugs, understanding the roles of electrostatic forces in the active sites of enzymes, and the formation of the chromophore in green and red fluorescent protein. He is the director of the Tuberculosis Related Research Program at Stony Brook. Tonge received both his BSc and PhD degrees from the University of Birmingham, England, in 1982 and 1986, respectively. Among his awards and honors are a SERC-NATO Postdoctoral Research Fellowship from the National Research Council, Canada, and an Alfred P. Sloan Research Fellowship received in 2001.
Megan Stephan
Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.