Jon Clardy

Last updated
Jon Clardy
Born
Washington, D.C.
NationalityAmerican
Alma mater Yale University (B.S.), Harvard University (Ph.D.)
Awards Ernest Guenther Award (1995)

Jon Clardy (born May 16, 1943, Washington, D.C., United States) is currently the Hsien Wu and Daisy Yen Wu professor of biological chemistry and molecular pharmacology at Harvard Medical School. [1] His research focuses on the isolation and structural characterization of natural products, and currently investigates the role of biologically active small molecules in mediating symbiotic interactions and disease. [2]

Contents

Biography

Clardy grew up in Arlington, Virginia, United States, the oldest of four children. He attended Yale University where he received a B.S. in 1964 and was elected to Phi Beta Kappa. While he was always captivated by biology, during college he became more interested in chemistry. He performed undergraduate research in organic synthesis, directed by R. Stephen Berry, with an emphasis on benzyne. [3] After graduating from Yale, he moved to Harvard University, where he received a Ph.D. in chemistry in 1969. He then accepted a faculty position in the Chemistry Department at Iowa State University, where he was affiliated with the Ames Laboratory. In 1978, he moved to the Chemistry Department at Cornell University where he stayed until 2002, when he moved to the Biological Chemistry and Molecular Pharmacology Department at Harvard Medical School. In 2004, he started the Ph.D. Program in Chemical Biology with Stuart Schreiber and Greg Verdine. [4] He also created, and continues to teach, a popular class entitled "Molecules of Life" for Harvard undergraduates who are not majoring in sciences.

While pursuing his Ph.D., Clardy met his wife Andrea Fleck, a Swarthmore College graduate, who is a writer. Her works include a children's book, two books about upstate New York, and plays that have been performed across the country. They have two sons.

Natural product discovery

Clardy's early research focused on the structure elucidation of natural products primarily by X-ray crystallography. Early on at Iowa State University Clardy established important collaborations with Bill Fenical, John Faulkner and Paul Scheuer, [5] which led to the structure elucidation of numerous marine natural products such as the anticancer agent bryostatin, [6] the insecticidal and antifungal jaspamide, diazonamide A and B, [7] and many others. Some of his most notable early work focused on the neurotoxins associated with "red tide" – which led to the determination of the three dimensional structures of saxitoxin, [8] of the gonyautoxin group, and the cyclic polyether brevetoxin B. [9] Upon moving to Cornell University, Clardy's research expanded to include a huge variety of non-marine organisms including, but not limited to, fungi, Actinomycetota and C. elegans . His longstanding interest in endophytic fungi led to the discovery of the selectively cytotoxic quinone torreyanic acid, the structurally diverse guanacastepenes, the antimycotic agent cryptocin, and many others.

Recently, Clardy has focused on symbiotic associations between bacteria and other organisms as rich sources of novel small molecules. [10] In collaboration with Cameron Currie, Clardy investigated associations between Actinomycetes and insects such as the southern pine beetle, ants and termites that led to the discovery of antifungal agents including dentigerumycin [11] [12] and mycangimycin. [13] [14] The study of chemical exchange in complex ecological interactions remains a central focus of the Clardy lab. [15]

X-ray crystallography of small molecule – protein interactions

Clardy, in collaboration with Stuart Schreiber and colleagues, obtained the crystal structure for both the FK506/FKBP12 and rapamycin/FKBP12 complexes. [16] Shortly thereafter Schreiber and Clardy went on to determine the structure of the FK506/rapamycin/FRAP complex – a groundbreaking study that revealed the ability of a cell-permeable small molecule to facilitate protein dimerization. [17] Vertex, a start-up pharmaceutical company, was founded to design a nontoxic version of FK506. [18] In collaboration with Walter Leal, Clardy and colleagues obtained an X-ray crystal structure for the volatile insect pheromone bombykol with its binding partner located on the antennae of female silkworm moths. [19] Besides further enhancing the understanding of this highly specific small-molecule-protein interaction, this study marked the first three-dimensional structure of an odorant-binding protein. [20]

eDNA

Clardy is also known for his work in elucidating natural products made by unculturable bacteria and is credited, along with Jo Handelsman and Robert M. Goodman, for pioneering the field of metagenomics. With Sean Brady, he developed a method to insert DNA directly from environmental DNA (eDNA) like soil, into cosmid libraries, search for biosynthetic gene clusters and identify the products of these genes. [21] Using this method they elucidated the structures of numerous antibiotics previously unattainable by traditional lab techniques, such as natural products derived from long-chain N-acyltyrosines. [22]

Related Research Articles

<span class="mw-page-title-main">DNA-binding protein</span> Proteins that bind with DNA, such as transcription factors, polymerases, nucleases and histones

DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, because it exposes more functional groups that identify a base pair. However, there are some known minor groove DNA-binding ligands such as netropsin, distamycin, Hoechst 33258, pentamidine, DAPI and others.

mTOR Mammalian protein found in Homo sapiens

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

Stuart L. Schreiber is a scientist at Harvard University and co-Founder of the Broad Institute. He has been active in chemical biology, especially the use of small molecules as probes of biology and medicine. Small molecules are the molecules of life most associated with dynamic information flow; these work in concert with the macromolecules that are the basis for inherited information flow.

In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. Immunophilins are traditionally classified into two families that differ in sequence and biochemical characteristics. These two families are: "cyclosporin-binding cyclophilins (CyPs)" and "FK506-binding proteins (FKBPs)". In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order.

<span class="mw-page-title-main">FKBP</span>

The FKBPs, or FK506 binding proteins, constitute a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes, ranging from yeast to humans, and function as protein folding chaperones for proteins containing proline residues. Along with cyclophilin, FKBPs belong to the immunophilin family.

<span class="mw-page-title-main">FKBP4</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 4 is a protein that in humans is encoded by the FKBP4 gene.

Sex pheromones are pheromones released by an organism to attract an individual of the same species, encourage them to mate with them, or perform some other function closely related with sexual reproduction. Sex pheromones specifically focus on indicating females for breeding, attracting the opposite sex, and conveying information on species, age, sex and genotype. Non-volatile pheromones, or cuticular contact pheromones, are more closely related to social insects as they are usually detected by direct contact with chemoreceptors on the antennae or feet of insects.

<span class="mw-page-title-main">FKBP1A</span> Protein and coding gene in humans

Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the FKBP1A gene. It is also commonly referred to as FKBP-12 or FKBP12 and is a member of a family of FK506-binding proteins (FKBPs).

<span class="mw-page-title-main">FKBP5</span> Protein-coding gene in humans

FK506 binding protein 5, also known as FKBP5, is a protein which in humans is encoded by the FKBP5 gene.

<span class="mw-page-title-main">FKBP1B</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase FKBP1B is an enzyme that in humans is encoded by the FKBP1B gene.

<span class="mw-page-title-main">FKBP3</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 3 also known as FKBP25 is a protein that in humans is encoded by the FKBP3 gene.

<span class="mw-page-title-main">GLMN</span> Protein-coding gene in the species Homo sapiens

Glomulin is a protein that in humans is encoded by the GLMN gene.

<span class="mw-page-title-main">FKBP2</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 2 is a protein that in humans is encoded by the FKBP2 gene.

<span class="mw-page-title-main">FKBP10</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 10 is a protein that in humans is encoded by the FKBP10 gene.

<span class="mw-page-title-main">FKBP6</span>

FK506 binding protein 6, also known as FKBP6, is a human gene. The encoded protein shows structural homology to FKBP immunophilins, which bind to the immunosuppressants FK506 and rapamycin.

<span class="mw-page-title-main">Netropsin</span> Chemical compound

Netropsin is a polyamide with antibiotic and antiviral activity. Netropsin was discovered by Finlay et al., and first isolated from the actinobacterium Streptomyces netropsis. It belongs to the class of pyrrole-amidine antibiotics.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

Gerald R. Crabtree is the David Korn Professor at Stanford University and an Investigator in the Howard Hughes Medical Institute. He is known for defining the Ca2+-calcineurin-NFAT signaling pathway, pioneering the development of synthetic ligands for regulation of biologic processes and discovering chromatin regulatory mechanisms involved in cancer and brain development. He is a founder of Ariad Pharmaceuticals, Amplyx Pharmaceuticals, and Foghorn Therapeutics.

<span class="mw-page-title-main">FK1012</span> Chemical compound

FK1012 is a dimer consisting of two molecules of FK506 (tacrolimus) linked via their vinyl groups. It is used as a research tool in chemically induced dimerization applications. FK506 binding proteins (FKBPs) do not normally form dimers but can be caused to dimerize in the presence of FK1012. Genetically engineered proteins based on FKBPs can be used to manipulate protein localization, signalling pathways and protein activation.

David Nathan Beratan is an American chemist and physicist, the R.J. Reynolds Professor of Chemistry at Duke University. He has secondary appointments in the departments of Physics and Biochemistry. He is the Director of the Center for Synthesizing Quantum Coherence, a NSF Phase I Center for Chemical Innovation.

References

  1. ↑ "BCMP | Department of Biological Chemistry & Molecular Pharmacology". Bcmp.med.harvard.edu. Retrieved 2013-09-28.
  2. ↑ "Jon Clardy | Clardy Laboratory". Clardy.med.harvard.edu. Retrieved 2013-09-28.
  3. ↑ Berry, R. S., Clardy, J. & Schafer, M. E. Benzyne. J. Am. Chem. Soc. 86, 2738–2739 (1964)
  4. ↑ "The Chemical Biologists | Harvard Magazine Mar-Apr 2005". Harvardmagazine.com. Retrieved 2013-09-28.
  5. ↑ The American Society of Pharmacognosy Newsletter. 1-3 (2004)
  6. ↑ Pettit, G. R. et al. Isolation and structure of bryostatin 1. J. Am. Chem. Soc. 104, 6846–6848 (1982)
  7. ↑ Lindquist, N., Fenical, W., Van Duyne, G. D. & Clardy, J. Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensis. J. Am. Chem. Soc. 113, 2303–2304 (1991)
  8. ↑ Schantz, E. J. et al. Structure of saxitoxin. J. Am. Chem. Soc. 97, 1238–1239 (1975)
  9. ↑ Lin, Y.-Y. et al. Isolation and structure of brevetoxin B from the' red tide' dinoflagellate Ptychodiscus brevis (Gymnodinium breve). J. Am. Chem. Soc. 103, 6773–6775 (1981)
  10. ↑ "Of beetles and bacteria | The Scientist Magazine". Archived from the original on 2013-10-02. Retrieved 2014-08-25.
  11. ↑ Oh, D.-C., Poulsen, M., Currie, C. R. & Clardy, J. Dentigerumycin: a bacterial mediator of an ant-fungus symbiosis. Nat Chem Biol 5, 391–393 (2009)
  12. ↑ Willson, E. & Yarnell, A. In Cahoots: Fungi, Ants, And Bacteria. Chemical & Engineering News 87, 15 (2009)
  13. ↑ Scott, J. J. et al. Bacterial protection of beetle-fungus mutualism. Science 322, 63 (2008)
  14. ↑ Drahl, C. Beetle Bacteria Wield An Antifungal Agent. Chemical & Engineering News 86, 47 (2008)
  15. ↑ "Jon Clardy". Academy.asm.org. Archived from the original on 2013-04-25. Retrieved 2013-09-28.
  16. ↑ Van Duyne, G.D., Standaert, R. F., Karplus, P. A., Schreiber. S.L., Clardy J. Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. Science 252, 839-842 (1991)
  17. ↑ Choi, J., Chen, J., Schreiber S. L., Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239-242 (1996)
  18. ↑ Billion Dollar Molecule: The Quest for the Perfect Drug, Barry Werth, 1994
  19. ↑ Sandler, B. H., Nikonova, L., Leal, W. S. & Clardy, J. Sexual attraction in the silkworm moth: structure of the pheromone-binding-protein-bombykol complex. Chemistry & Biology 7, 143–151 (2000)
  20. ↑ Sandler, B. H., Nikonova, L., Leal, W. S. & Clardy, J. Sexual attraction in the silkworm moth: structure of the pheromone-binding-protein–bombykol complex. Chemistry & Biology 7, 143–151 (2000)
  21. ↑ Brady, S. F., Chao, C. J. & Clardy, J. New Natural Product Families from an Environmental DNA (eDNA) Gene Cluster. J. Am. Chem. Soc. 124, 9968–9969 (2002)
  22. ↑ Brady, S. F., Chao, C. J. & Clardy, J. Long-chain N-acyltyrosine syntheses from environmental DNA. Appl. Environ. Microbiol. 70, 6865–6870 (2004)
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