STRUCTURAL STUDIES OF AIDS-RELATED ENZYMES AND OTHER PATHOGENIC TARGETS

艾滋病相关酶和其他致病靶标的结构研究

• 批准号: 8362410
• 负责人: Vivian Cody
• 金额: $ 0.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362410
• 关键词: Acquired Immunodeficiency Syndrome; Area; Biological; Complex; Data; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Dihydropteroate Synthase; Dimerization; Drug resistance; Enzymes; Escherichia coli; Funding; Goals; Grant; Human; Immunocompromised Host; Investigation; Medical Research; Minnesota; Mutation; Nanotubes; National Center for Research Resources; Opportunistic Infections; Patients; Pneumocystis; Pneumocystis carinii Pneumonia; Principal Investigator; Radiation; Request for Proposals; Research; Research Infrastructure; Research Institute; Resolution; Resources; Role; Site; Site-Directed Mutagenesis; Source; Structure; Therapeutic Agents; Time; United States National Institutes of Health; Variant; cost; design; dimer; inhibitor/antagonist; mortality; novel; pathogen; programs; structural biology; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Cody lab at the Hauptman-Woodward Medical Research Institute (HWI) has a multi-faceted research program that focuses on understanding the role of site specific residues in the design of selective inhibitors of pathogens such as Pneumocystis (Pc), a major cause of opportunistic infection and mortality in immunocompromised patients, particularly those with AIDS. Pneumocystis jirovecii (pj) is the causative agent of Pneumocystis pneumonia (PcP), one of the most frequent and severe opportunistic infections in immunocompromised patients. In this proposal, we request beamtime to develop complementary areas of biological structural research. Recent studies show that mutations accumulate over time in the target enzymes, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) from Pneumocystis, potentially giving rise to drug resistance. A major goal of this project is to characterize pjDHFR and pjDHPS and their variants in order to design effective inhibitors that have potential as therapeutic agents for the treatment of PcP. Site-directed mutagenesis studies on DHFR enzymes are under investigation to determine the role of specific residues in modulating DHFR inhibitor potency and in conferring drug-resistance to pjDHFR as observed in AIDS patient isolates. Structures of human DHFR inhibitor complexes are under investigation to compare their structures with those of the Pneumocystis DHFR enzymes. We require the use of synchrotron radiation to determine high-resolution details of these inhibitor complexes. In another collaborative study (Wagner, Univ. Minnesota), E. coli DHFR dimerization complexes are being investigated to design novel nanotube assemblies. Structural data are needed to validate dimerization assembly and to determine how mutations at the dimer interface modulate nanotube assembly. Sychrotron time is needed as these crystals tend to be small and diffract modestly.

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