eBriefing

Chemical Genetics

Chemical Genetics
Reported by
Megan Stephan

Posted March 14, 2010

Overview

The genomic revolution has resulted in the discovery of an almost overwhelming number of new genes and their protein products. The biologist's challenge now is how to work through this mass of data efficiently, uncovering what all these genes and proteins are doing in the cell. Enter the chemical biologist. His or her mission is to develop small molecules that can act as probes of protein function. These molecules can be used on a large, massively parallel scale that matches the large genomic dataset, or they can be used to provide highly detailed information about the functions of very specific proteins. Together, these approaches comprise what is now known as "chemical genetics."

On June 7, 2005, the Chemical Biology Discussion Group held a symposium that highlighted the great diversity of approaches chemical biologists are taking to address these tasks. Some researchers described very specialized projects, aimed at developing highly selective chemical inhibitors for key cellular proteins, while others discussed general methodologies to be used in large scale high-throughput studies. Others described small molecule tools that can be used to both manipulate and measure the behavior of proteins in living cells, to better understand their functions in a real world setting.

Use the tabs above to view the meeting report and multimedia presentations.

Web Sites

Chembank Initiative for Chemical Genetics
A freely available collection of data about small molecules and resources for studying their properties, especially their effects on biology.

HHMI Biointeractive Animation Console: Small molecule microarrays
Animation that shows how small molecule microarrays are made and used.

HHMI Biointeractive Animation Console: Proteasome
A 3D animation showing how proteins in the cell are tagged for disposal and degraded by the proteasome.

Rockefeller University: Protein translocation animation
Highly detailed and scientifically accurate animation of cotranslational translocation.

Nature Chemical Biology
This new journal cosponsored this meeting in honor of its debut issue.

The protein kinase resource
A compendium of information on the protein kinase family of enzymes.

What is chemical genetics?
Brief description of chemical genetics on the Howard Hughes Medical Institute website.

Yale Chemical Biology Symposium
A day-long event, held in early May, that highlights new advances at the interface of chemistry and biology.

Researchers at the following labs participated in this event. All of these sites offer papers and other publications as PDF files.

Craig Crews Laboratory
Young-Tae Chang Laboratory
Derek Tan Laboratory


Books

Darvas, F, A. Guttman & G. Dorman, Eds. 2004. Chemical Genomics. Marcel Dekker, New York.

Ross, J., I. Schreiber & M. O. Vlad. 2005. Determination of Complex Reaction Mechanisms: Analysis of Chemical, Biological, and Genetic Networks. Oxford University Press, New York.


Journal Articles

Small Molecule Inhibitors of Signaling and Secretion

Boger, D. L., H. Keim, B. Oberhauser et al. 1999. Total synthesis of HUN-7293. J. Am. Chem. Soc. 121: 6197-6205.

Chen, Y., M. Bilban, C.A. Foster & D. L. Boger. 2002. Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides. J. Am. Chem. Soc. 124: 5431-5440.

Cohen, M. S., C. Zhang, K. M. Shokat & J. Taunton. 2005. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308: 1318-1320.

Frodin, M., C. J. Jensen, K. Merienne, S. Gammeltoft. 2000. A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1. EMBO J. 19: 2924-2934.

Garrison, J. L., E. J. Kunkel, R. S. Hegde, J. Taunton. 2005. A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum. Nature 436:285-289.

Manning, G., D. B. Whyte, R. Martinez et al. 2002. The protein kinase complement of the human genome. Science 298: 1912-1934.

Menetret, J. F, A. Neuhof, D. G. Morgan et al. 2000. The structure of ribosome-channel complexes engaged in protein translocation. Mol. Cell. 6: 1219-1232.

Van den Berg, B., W. M. Clemons, I. Collinson et al. 2004. X-ray structure of a protein-conducting channel. Nature 427: 36-44.

White, S. H. & G. von Heijne. 2004. The machinery of membrane protein assembly. Curr. Opin. Struct. Biol. 14: 397-404. (PDF, 448 MB) Full Text

Small-Molecule Inhibition of Siderophore Biosynthesis

Braun, V. & M. Braun. 2002. Iron transport and signaling in Escherichia coli. FEBS Lett. 529: 78-85.

Crosa, J. H. & C. T. Walsh. 2002. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66: 223-249. Full Text

Ferreras, J. A., J.-S. Ryu, F. Di Lello et al. 2005. Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nature Chem. Biol. 1: 29-32.

Potuzak, J. S., S. B. Moilanen & D. S. Tan. 2004. Discovery and applications of small molecule probes for studying biological processes. Biotechnol. Genet. Eng. Rev. 21: 11-78.

Quadri, L. E. 2000. Assembly of aryl-capped siderophores by modular peptide synthetases and polyketide synthases. Mol. Microbiol. 37: 1-12. Full Text

Ratledge, C. & L. G. Dover. 2000. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54: 881-941.

Shang, S. & D. S. Tan. 2005. Advancing chemistry and biology through diversity-oriented synthesis of natural product-like libraries. Curr. Opin. Chem. Biol. 9: 248-258.

Tagged Small Molecule Libraries for Chemical Genetics

Bork, J. T., J. W. Lee & Y. T. Chang. 2004. The combinatorial synthesis of purine, pyrimidine, and triazine-based libraries. QSAR Comb. Sci. 23: 245-260.

Khersonsky, S. M. & Y. T. Chang. 2004. Forward chemical genetics: library scaffold design. Comb. Chem. High Throughput Screen. 7: 645-652.

Khersonsky, S. M. & Y. T. Chang. 2004. Strategies for facilitated forward chemical genetics. ChemBioChem. 5: 903-908.

Khersonsky, S. M., D. W. Jung, T. W. Kang et al. 2003. Facilitated forward chemical genetics using tagged triazine library and zebrafish embryo screening. J. Am. Chem. Soc. 125: 11804-11805.

Mitsopoulos, G., D. P. Walsh & Y. T. Chang. 2004. Tagged library approach to chemical genomics and proteomics. Curr. Opin. Chem. Biol. 8: 26-32.

Uttamchandani, M., D. P. Walsh, S. M. Khersonsky et al. 2004. Microarrays of tagged combinatorial triazine libraries in the discovery of small molecule ligands of human IgG. J. Comb. Chem. 6: 862-868.

Uttamchandani, M., D. P. Walsh, S. Q. Yao & Y. T. Chang. 2005. Small molecule microarrays: recent advances and applications. Curr. Opin. Chem. Biol. 9: 4-13.

Wang, S., T. Sim, Y. S. Kim & Y. T. Chang. 2004. Tools for target identification and validation. Curr. Opin. Chem. Biol. 8: 371-377.

Williams, D., D. W. Jung, S. M. Khersonsky et al. 2004. Forward chemical genetics: Phenotypic screening of a tagged triazine library of small molecules reveals the F1F0 mitochondrial ATPase as a drug target for correcting oculocutaneous albinism type 2. J. Chem. Biol. 11: 1251-1259. (PDF, 501 MB) Full Text

Photocontrol of Proteins in Live Cells

Giriat, I. & T. W. Muir. 2003. Protein semi-synthesis in living cells. J. Am. Chem. Soc. 125: 7180-7181.

Hahn, M. E. & T. W. Muir. 2005. Manipulating proteins with chemistry: a cross-section of chemical biology. Trends Biochem. Sci. 30: 26-34. (PDF, 1.31 MB) Full Text

Hahn, M. E. & T. W. Muir. 2004. Photocontrol of Smad2, a multiphosphorylated cell-signaling protein, through caging of activating phosphoserines. Angew Chem. Int. Ed. 43: 5800-5803.

Mootz, H. D., E. S. Blum, A. B. Tyszkiewicz & T. W. Muir. 2003. Conditional protein splicing: A new tool to control protein structure and function in vitro and in vivo. J. Am. Chem. Soc. 125: 10561-10569.

Pellois, J. P., M. E. Hahn, T. W. Muir. 2003. Photo-control of the activity of proteins via caging of their C- terminus. Biopolymers 71: 352-354.

Pellois, J. P., M. E. Hahn & T. W. Muir. 2004. Simultaneous triggering of protein activity and fluorescence. J. Am. Chem. Soc. 126: 7170-7171.

Shi, J. X. & T. W. Muir. 2005. Development of a tandem protein trans-splicing system based on native and engineered split inteins. J. Am. Chem. Soc. 127: 6198-6206.

Wu, J. W., M. Hu & J. J. Chai. 2001. Crystal structure of a phosphorylated Smad2: Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol. Cell. 8: 1277-1289.

Proteolysis Targeting Chimera Molecules, or Protacs

Brdlik, C. & C. M. Crews. 2004. A single amino acid residue defines inhibitor specificity for the methionine aminopeptidase family. J. Biol. Chem. 279: 9475-9480. Full Text

Crews, C. M.. 2003. Feeding the machine: mechanisms of proteasome-catalyzed degradation of ubiquinated proteins. Curr. Opin. Chem. Biol. 7: 534-539.

Myung, J., K. Kim & C. M. Crews. 2001. Proteasome inhibition: mechanism and inhibitors. Med. Res. Rev. 21: 245-273. (PDF, 513 KB) Full Text

Sakamoto, K. M., K. B. Kim, A. Kumagai et al. 2001. Protacs: chimeric molecules that target proteins to the SCF complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 98: 8554-8559. Full Text

Sakamoto, K. M., K. Kim, R. Verma et al. 2003. Development of protacs to target cancer: promoting proteins for ubiquitination and degradation. Mol. Cell. Proteomics. 2: 1350-1358. Full Text

Schneekloth, J. S. Jr. & C. M. Crews. 2005. Chemical approaches to controlling intracellular protein degradation. Chembiochem. 6: 40-46.

Schneekloth, J.S. Jr., F. Fonseca, M. Koldobskiy et al. 2004. Chemical genetic control of protein levels: selective in vivo targeted degradation. J. Am. Chem. Soc. 126: 3748-3754.

Speakers

Jack Taunton, PhD

University of California, San Francisco
e-mail | web site | publications

Jack Taunton is an assistant professor in the department of cellular and molecular biology at the University of California at San Francisco, where he established his laboratory in 2000. His research program is two-fold, including study of endosome movement powered by membrane-dependent actin assembly, and study of cellular processes using small molecules.

Taunton was the recipient of a Searle Scholar award in 2002 and an Alfred P. Sloan fellowship in 2003. He did his PhD work with Stuart Schreiber at Harvard University, where he worked on the total synthesis of dimethyldynemicin methyl ester, an antitumor agent, and on the purification and cloning of histone deacetylase.

Jae-Sang Ryu, PhD

Memorial Sloan-Kettering Cancer Center
e-mail | web site | publications

Jae-Sang Ryu is a postdoctoral associate in Derek Tan's laboratory at Memorial Sloan Kettering Cancer Institute. His work on siderophore biosynthesis inhibitors is part of a larger research program directed at discovering novel small molecule inhibitors of protein function.

Ryu received a Master's degree from Seoul National University College of Pharmacy, Korea, and a PhD in organic chemistry from Northwestern University in 2003. His doctoral work, mentored by Tobin J. Marks, was on organolanthanide-catalyzed hydroamination and the synthetic application to natural alkaloids. In the fall of 2005, he will take a position as an assistant professor at Ewha Womans University College of Pharmacy in Korea.

Daniel P. Walsh, PhD

New York University
e-mail | web site

Daniel P. Walsh was a graduate student when he gave his talk on tagged chemical libraries, but has since defended his thesis and received his PhD. His thesis work was done in the laboratory of Young-Tae Chang at New York University, where he has studied since December of 2000. Chang's research program is focused on the development of synthetic combinatorial laboratories for high throughput identification of protein inhibitors and drug candidates.

Previously, Walsh did research with Paul T. Buonora of the University of Scranton in Pennsylvania. In August 2005, he is joining the New York City Department of Environmental Protections HAZ-MAT Response Unit.

Jean-Philippe Pellois, PhD

The Rockefeller University
e-mail | web site | publications

Jean-Philippe Pellois has been a postdoctoral associate in the laboratory of Tom Muir at The Rockefeller University since 2003. Pellois' work on photo-activatable proteins is one of a number of chemistry-driven technologies developed in the Muir laboratory for protein function studies. Pellois' PhD work, on the synthesis and applications of high density peptide microarrays, was carried out under Xiaolian Gao at the University of Houston, Texas. Pellois also holds a Master's degree from CPE Lyon, France. He plans to look for an academic position in the fall of 2005.

Jonathan Gough, PhD

Yale University
e-mail | web site | publications

Jonathan Gough works in the laboratory of Craig Crews in the department of molecular, cellular, and development biology at Yale University. He completed his doctoral work in the department of chemistry at Syracuse University.


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.