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X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor

Swain, Amy L. and Miller, Maria M. and Green, Jeremy and Rich, Daniel H. and Schneider, Jens and Kent, Stephen B. H. and Wlodawer, Alexander (1990) X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 87 (22). pp. 8805-8809. ISSN 0027-8424. https://resolver.caltech.edu/CaltechAUTHORS:20150108-153641400

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Abstract

The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-ψ[CH(OH)CH_2N]-Pro-Ile-Val-OMe; the K_i is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-Å resolution by using restrained least squares with rms deviations in bond lengths of 0.02 Å and bond angles of 4. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.87.22.8805DOIArticle
http://www.pnas.org/content/87/22/8805PublisherArticle
Additional Information:© 1990 National Academy of Sciences. Communicated by Bruce Merrifield, August 2, 1990. We thank Annaliese Palmer for providing computed coordinate sets for JG-365. The Advanced Scientific Computing Laboratory (Frederick Cancer Research and Development Center) provided a substantial allocation of time on their CRAY X-MP supercomputer. Research sponsored in part by the National Cancer Institute (Department of Health and Human Services) Contract NO1-CO-74101 with ABL, by funds from the National Science Foundation Biological Instrumentation Division to S.B.H.K., and by National Institutes of Health Grant AI27302 to D.H.R. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
National Cancer InstituteNO1-CO-74101
NSFUNSPECIFIED
NIHAI27302
Subject Keywords:AIDS; retrovirus; diastereomer; tetrahedral intermediate; symmetry
Issue or Number:22
Record Number:CaltechAUTHORS:20150108-153641400
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150108-153641400
Official Citation:Swain, A. L., Miller, M. M., Green, J., Rich, D. H., Schneider, J., Kent, S. B., & Wlodawer, A. (1990). X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor. Proceedings of the National Academy of Sciences, 87(22), 8805-8809. doi: 10.1073/pnas.87.22.8805
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53407
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:09 Jan 2015 23:28
Last Modified:03 Oct 2019 07:49

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