Abstract

Immunophilins and related proteins participate in many fundamental biological processes, and this project's overall goal is analyzing these processes in structural terms. In addition to providing a basic structural understanding of these important proteins, the project has practical implications for prevent graft versus. host disease in transplant patients, alleviating autoimmune diseases such as rheumatoid arthritis and insulin- dependent diabetes, and developing small molecules for regulated gene therapy. Separate projects include: Structures of the large immunophilins FKBP51 and FKB952 along with their partners in the steroid receptor complex Hip and Hop. Structure of FRAP, a member of the ATM family of proteins involved in cell cycle checkpoints and DNA repair. Structure of dihydroorotate dehydrogenase, the protein target of the rheumatoid arthritis drug leflunomide (Arava) and the anti- cancer agent brequinar. Structure of the dimerizing agents based on FKBP12-rapamycin- FRB that are clinically useful in small molecule regulated gene therapy. Structures such as fyn SH2-pYEEI/FK506-FKBP52 that illustrate the concept of using borrowed endogenous proteins to moderate the binding of hybrid small molecules.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA059021-08
Application #
6042559
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Lees, Robert G
Project Start
1992-07-10
Project End
2003-12-31
Budget Start
2000-01-20
Budget End
2000-12-31
Support Year
8
Fiscal Year
2000
Total Cost
$234,684
Indirect Cost

  Institution

Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850

  Publications

Ramadhar, Timothy R; Beemelmanns, Christine; Currie, Cameron R et al. (2014) Bacterial symbionts in agricultural systems provide a strategic source for antibiotic discovery. J Antibiot (Tokyo) 67:53-8
Wieland Brown, Laura C; Acker, Michael G; Clardy, Jon et al. (2009) Thirteen posttranslational modifications convert a 14-residue peptide into the antibiotic thiocillin. Proc Natl Acad Sci U S A 106:2549-53
Fischbach, Michael A; Walsh, Christopher T; Clardy, Jon (2008) The evolution of gene collectives: How natural selection drives chemical innovation. Proc Natl Acad Sci U S A 105:4601-8
Mazitschek, Ralph; Patel, Vishal; Wirth, Dyann F et al. (2008) Development of a fluorescence polarization based assay for histone deacetylase ligand discovery. Bioorg Med Chem Lett 18:2809-12
Junker, Lauren M; Clardy, Jon (2007) High-throughput screens for small-molecule inhibitors of Pseudomonas aeruginosa biofilm development. Antimicrob Agents Chemother 51:3582-90
Schmitz, Katja; Haggarty, Stephen J; McPherson, Olivia M et al. (2007) Detecting binding interactions using microarrays of natural product extracts. J Am Chem Soc 129:11346-7
Lautenschlager, Catherine; Leal, Walter S; Clardy, Jon (2007) Bombyx mori pheromone-binding protein binding nonpheromone ligands: implications for pheromone recognition. Structure 15:1148-54
Fischbach, Michael A; Clardy, Jon (2007) One pathway, many products. Nat Chem Biol 3:353-5
Clardy, Jon; Brady, Sean F (2007) Cyclic AMP directly activates NasP, an N-acyl amino acid antibiotic biosynthetic enzyme cloned from an uncultured beta-proteobacterium. J Bacteriol 189:6487-9
Schroeder, Frank C; Gibson, Donna M; Churchill, Alice C L et al. (2007) Differential analysis of 2D NMR spectra: new natural products from a pilot-scale fungal extract library. Angew Chem Int Ed Engl 46:901-4

Showing the most recent 10 out of 28 publications