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Title: Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease

Abstract

Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K{sub i}, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place.

Authors:
; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (Debrecen)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNOTHERNIHNCINIAID
OSTI Identifier:
1040913
Resource Type:
Journal Article
Journal Name:
FEBS J.
Additional Journal Information:
Journal Volume: 278; Journal Issue: (22) ; 11, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AIDS VIRUS; CRYSTAL STRUCTURE; ENZYMES; LEUKEMIA; RESOLUTION; WATER

Citation Formats

Li, Mi, Gustchina, Alla, Matúz, Krisztina, Tözsér, Jozsef, Namwong, Sirilak, Goldfarb, Nathan E., Dunn, Ben M., Wlodawer, Alexander, NCI), Florida), and Suan Sunandha). Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease. United States: N. p., 2012. Web. doi:10.1111/j.1742-4658.2011.08364.x.
Li, Mi, Gustchina, Alla, Matúz, Krisztina, Tözsér, Jozsef, Namwong, Sirilak, Goldfarb, Nathan E., Dunn, Ben M., Wlodawer, Alexander, NCI), Florida), & Suan Sunandha). Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease. United States. doi:10.1111/j.1742-4658.2011.08364.x.
Li, Mi, Gustchina, Alla, Matúz, Krisztina, Tözsér, Jozsef, Namwong, Sirilak, Goldfarb, Nathan E., Dunn, Ben M., Wlodawer, Alexander, NCI), Florida), and Suan Sunandha). Tue . "Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease". United States. doi:10.1111/j.1742-4658.2011.08364.x.
@article{osti_1040913,
title = {Structural and biochemical characterization of the inhibitor complexes of xenotropic murine leukemia virus-related virus protease},
author = {Li, Mi and Gustchina, Alla and Matúz, Krisztina and Tözsér, Jozsef and Namwong, Sirilak and Goldfarb, Nathan E. and Dunn, Ben M. and Wlodawer, Alexander and NCI) and Florida) and Suan Sunandha)},
abstractNote = {Interactions between the protease (PR) encoded by the xenotropic murine leukemia virus-related virus and a number of potential inhibitors have been investigated by biochemical and structural techniques. It was observed that several inhibitors used clinically against HIV PR exhibit nanomolar or even subnanomolar values of K{sub i}, depending on the exact experimental conditions. Both TL-3, a universal inhibitor of retroviral PRs, and some inhibitors originally shown to inhibit plasmepsins were also quite potent, whereas inhibition by pepstatin A was considerably weaker. Crystal structures of the complexes of xenotropic murine leukemia virus-related virus PR with TL-3, amprenavir and pepstatin A were solved at high resolution and compared with the structures of complexes of these inhibitors with other retropepsins. Whereas TL-3 and amprenavir bound in a predictable manner, spanning the substrate-binding site of the enzyme, two molecules of pepstatin A bound simultaneously in an unprecedented manner, leaving the catalytic water molecule in place.},
doi = {10.1111/j.1742-4658.2011.08364.x},
journal = {FEBS J.},
number = (22) ; 11, 2011,
volume = 278,
place = {United States},
year = {2012},
month = {10}
}