Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

Heaslet, Holly; Lin, Ying-Chuan; Tam, Karen; Torbett, Bruce E.; Elder, John H.; Stout, C. David

doi:10.1186/1742-4690-4-1

Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

Journal Article · Mon Jan 08 23:00:00 EST 2007 · Retrovirology

DOI:https://doi.org/10.1186/1742-4690-4-1· OSTI ID:1626604

Heaslet, Holly ^[1]; Lin, Ying-Chuan ^[2]; Tam, Karen ^[2]; Torbett, Bruce E. ^[3]; Elder, John H. ^[2]; Stout, C. David ^[2]

Pfizer Global Research & Development, Ann Arbor, MI (United States); DOE/OSTI
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular Biology
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular and Experimental Medicine

We have obtained the 1.7 Å crystal structure of FIV protease (PR) in which 12 critical residues around the active site have been substituted with the structurally equivalent residues of HIV PR (12X FIV PR). The chimeric PR was crystallized in complex with the broad-based inhibitor TL-3, which inhibits wild type FIV and HIV PRs, as well as 12X FIV PR and several drug-resistant HIV mutants. Biochemical analyses have demonstrated that TL-3 inhibits these PRs in the order HIV PR > 12X FIV PR > FIV PR, with Ki values of 1.5 nM, 10 nM, and 41 nM, respectively. Comparison of the crystal structures of the TL-3 complexes of 12X FIV and wild-type FIV PR revealed the formation of additional van der Waals interactions between the enzyme inhibitor in the mutant PR. The 12X FIV PR retained the hydrogen bonding interactions between residues in the flap regions and active site involving the enzyme and the TL-3 inhibitor in comparison to both FIV PR and HIV PR. However, the flap regions of the 12X FIV PR more closely resemble those of HIV PR, having gained several stabilizing intra-flap interactions not present in wild type FIV PR. These findings offer a structural explanation for the observed inhibitor/substrate binding properties of the chimeric PR.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1626604

Journal Information:: Retrovirology, Journal Name: Retrovirology Journal Issue: 1 Vol. 4; ISSN 1742-4690

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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