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Title: Protein conformational dynamics in the mechanism of HIV-1 protease catalysis

We have used chemical protein synthesis and advanced physical methods to probe dynamics-function correlations for the HIV-1 protease, an enzyme that has received considerable attention as a target for the treatment of AIDS. Chemical synthesis was used to prepare a series of unique analogues of the HIV-1 protease in which the flexibility of the 'flap' structures (residues 37-61 in each monomer of the homodimeric protein molecule) was systematically varied. These analogue enzymes were further studied by X-ray crystallography, NMR relaxation, and pulse-EPR methods, in conjunction with molecular dynamics simulations. We show that conformational isomerization in the flaps is correlated with structural reorganization of residues in the active site, and that it is preorganization of the active site that is a rate-limiting factor in catalysis.
Authors:
; ; ; ; ; ;  [1] ;  [2] ;  [2]
  1. (GSU)
  2. (
Publication Date:
OSTI Identifier:
1033784
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; Journal Volume: 108; Journal Issue: (52) ; 12, 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
NSFDOE - BIOLOGICAL AND ENVIRONMENTAL RESEARCH
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AIDS VIRUS; CATALYSIS; CRYSTALLOGRAPHY; ENZYMES; FLEXIBILITY; ISOMERIZATION; MONOMERS; PROTEINS; RELAXATION; RESIDUES; SYNTHESIS