This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.To investigate mechanisms of catalysis, allosteric regulation, and drug interactions of CTP synthetases (CTPSs), we will solve structures from a variety of sources in their apo, substrate-bound,and nucleotide-regulated forms. CTPSs are key conserved nucleotide biosynthesic enzymes and are targets for anti-neoplastic,anti-fungal,and anti-parasitic agents. CTPS catalyzes an ATP-dependent aminotransfer reaction from glutamine to UTP in the last step of pyrimidine biosynthesis. In addition, EcCTPS is repressed by its product, CTP, but is activated by GTP,and regulated by phosphorylation in yeast. We recently solved the 2.3 resolution structure of the Apo E.coli enzyme (EcCTPS), the first enzyme in this class. To identify ligand-binding sites, to map the atomic level interactions, and to investigate regulatory mechanisms, we will determine the structures key ligand CTPS complexes. In addition, we will also determine the CTPS structures in complex with existing thereapeutic compounds to understand mode of action and the evolution of resistance. Finally, the structures of human, yeast, T. brucei, and Chlamydia enzymes will provide substrates for structure-based drug design of species-specific therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-28
Application #
7597989
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2007-03-01
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
28
Fiscal Year
2007
Total Cost
$5,020
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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