skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease

Abstract

Crystal structures of inactive variants of HIV-1 protease bound to peptides have revealed how the enzyme recognizes its endogenous substrates. The best of the known substrates is, however, a nonnatural substrate that was identified by directed evolution. The crystal structure of the complex between this substrate and the D25N variant of the protease is reported at a resolution of 1.1 Å. The structure has several unprecedented features, especially the formation of additional hydrogen bonds between the enzyme and the substrate. This work expands the understanding of molecular recognition by HIV-1 protease and informs the design of new substrates and inhibitors.

Authors:
;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1499760
Resource Type:
Journal Article
Journal Name:
Acta Crystallographica. Section D. Structural Biology
Additional Journal Information:
Journal Volume: 74; Journal Issue: 7; Journal ID: ISSN 2059-7983
Publisher:
IUCr
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Windsor, Ian W., and Raines, Ronald T. A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease. United States: N. p., 2018. Web. doi:10.1107/S2059798318006691.
Windsor, Ian W., & Raines, Ronald T. A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease. United States. doi:10.1107/S2059798318006691.
Windsor, Ian W., and Raines, Ronald T. Wed . "A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease". United States. doi:10.1107/S2059798318006691.
@article{osti_1499760,
title = {A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease},
author = {Windsor, Ian W. and Raines, Ronald T.},
abstractNote = {Crystal structures of inactive variants of HIV-1 protease bound to peptides have revealed how the enzyme recognizes its endogenous substrates. The best of the known substrates is, however, a nonnatural substrate that was identified by directed evolution. The crystal structure of the complex between this substrate and the D25N variant of the protease is reported at a resolution of 1.1 Å. The structure has several unprecedented features, especially the formation of additional hydrogen bonds between the enzyme and the substrate. This work expands the understanding of molecular recognition by HIV-1 protease and informs the design of new substrates and inhibitors.},
doi = {10.1107/S2059798318006691},
journal = {Acta Crystallographica. Section D. Structural Biology},
issn = {2059-7983},
number = 7,
volume = 74,
place = {United States},
year = {2018},
month = {6}
}

Works referenced in this record:

Kinetic and modeling studies of S3-S3' subsites of HIV proteinases
journal, May 1992

  • Tozser, Jozsef; Weber, Irene T.; Gustchina, Alla
  • Biochemistry, Vol. 31, Issue 20
  • DOI: 10.1021/bi00135a008

Fluorogenic Assay for Inhibitors of HIV-1 Protease with Sub-picomolar Affinity
journal, August 2015

  • Windsor, Ian W.; Raines, Ronald T.
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep11286

Nine Crystal Structures Determine the Substrate Envelope of the MDR HIV-1 Protease
journal, March 2011


The Choreography of HIV-1 Proteolytic Processing and Virion Assembly
journal, October 2012

  • Lee, Sook-Kyung; Potempa, Marc; Swanstrom, Ronald
  • Journal of Biological Chemistry, Vol. 287, Issue 49
  • DOI: 10.1074/jbc.R112.399444

Identification of Efficiently Cleaved Substrates for HIV-1 Protease Using a Phage Display Library and Use in Inhibitor Development
journal, September 2000

  • Beck, Zachary Q.; Hervio, Laurence; Dawson, Philip E.
  • Virology, Vol. 274, Issue 2
  • DOI: 10.1006/viro.2000.0420

Rate-determining Steps in HIV-1 Protease Catalysis: THE HYDROLYSIS OF THE MOST SPECIFIC SUBSTRATE
journal, December 1996

  • Szeltner, Zoltán; Polgár, László
  • Journal of Biological Chemistry, Vol. 271, Issue 50
  • DOI: 10.1074/jbc.271.50.32180

Catalytic efficiency and vitality of HIV-1 proteases from African viral subtypes
journal, May 2001

  • Velazquez-Campoy, A.; Todd, M. J.; Vega, S.
  • Proceedings of the National Academy of Sciences, Vol. 98, Issue 11
  • DOI: 10.1073/pnas.111152698

Computational design and experimental study of tighter binding peptides to an inactivated mutant of HIV‐1 protease
journal, January 2008

  • Altman, Michael D.; Nalivaika, Ellen A.; Prabu‐Jeyabalan, Moses
  • Proteins: Structure, Function, and Bioinformatics, Vol. 70, Issue 3
  • DOI: 10.1002/prot.21514

Strength of a bifurcated H bond
journal, March 2014

  • Feldblum, E. S.; Arkin, I. T.
  • Proceedings of the National Academy of Sciences, Vol. 111, Issue 11
  • DOI: 10.1073/pnas.1319827111

Variability at Human Immunodeficiency Virus Type 1 Subtype C Protease Cleavage Sites: an Indication of Viral Fitness?
journal, August 2003


Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Dynamics of Preferential Substrate Recognition in HIV-1 Protease: Redefining the Substrate Envelope
journal, July 2011

  • Özen, Ayşegül; Haliloğlu, Türkan; Schiffer, Celia A.
  • Journal of Molecular Biology, Vol. 410, Issue 4
  • DOI: 10.1016/j.jmb.2011.03.053

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy
journal, January 2003


Substrate Shape Determines Specificity of Recognition for HIV-1 Protease
journal, March 2002


How does a symmetric dimer recognize an asymmetric substrate? a substrate complex of HIV-1 protease
journal, September 2000

  • Prabu-Jeyabalan, Moses; Nalivaika, Ellen; Schiffer, Celia A.
  • Journal of Molecular Biology, Vol. 301, Issue 5
  • DOI: 10.1006/jmbi.2000.4018

Programming the Rous Sarcoma Virus Protease to Cleave New Substrate Sequences
journal, May 1996

  • Ridky, Todd W.; Bizub-Bender, Diane; Cameron, Craig E.
  • Journal of Biological Chemistry, Vol. 271, Issue 18
  • DOI: 10.1074/jbc.271.18.10538

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925