Document Detail

Local conformational stability of HIV-1 gp120 in unliganded and CD4-bound states as defined by amide hydrogen/deuterium exchange.
MedLine Citation:
PMID:  20660185     Owner:  NLM     Status:  MEDLINE    
The binding reaction of the HIV-1 gp120 envelope glycoprotein to the CD4 receptor involves exceptional changes in enthalpy and entropy. Crystal structures of gp120 in unliganded and various ligand-bound states, meanwhile, reveal an inner domain able to fold into diverse conformations, a structurally invariant outer domain, and, in the CD4-bound state, a bridging sheet minidomain. These studies, however, provide only hints as to the flexibility of each state. Here we use amide hydrogen/deuterium exchange coupled to mass spectrometry to provide quantifications of local conformational stability for HIV-1 gp120 in unliganded and CD4-bound states. On average, unliganded core gp120 displayed >10,000-fold slower exchange of backbone-amide hydrogens than a theoretically unstructured protein of the same composition, with binding by CD4 reducing the rate of gp120 amide exchange a further 10-fold. For the structurally constant CD4, alterations in exchange correlated well with alterations in binding surface (P value = 0.0004). For the structurally variable gp120, however, reductions in flexibility extended outside the binding surface, and regions of expected high structural diversity (inner domain/bridging sheet) displayed roughly 20-fold more rapid exchange in the unliganded state than regions of low diversity (outer domain). Thus, despite an extraordinary reduction in entropy, neither unliganded gp120 nor free CD4 was substantially unstructured, suggesting that most of the diverse conformations that make up the gp120 unliganded state are reasonably ordered. The results provide a framework for understanding how local conformational stability influences entropic change, conformational diversity, and structural rearrangements in the gp120-CD4 binding reaction.
Leopold Kong; Chih-Chin Huang; Stephen J Coales; Kathleen S Molnar; Jeff Skinner; Yoshitomo Hamuro; Peter D Kwong
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2010-07-21
Journal Detail:
Title:  Journal of virology     Volume:  84     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-08     Completed Date:  2010-09-28     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10311-21     Citation Subset:  IM    
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3027, USA.
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MeSH Terms
Amino Acid Sequence
Antigens, CD4 / metabolism*
Crystallography, X-Ray
Deuterium Exchange Measurement
HIV Envelope Protein gp120 / chemistry*,  genetics,  metabolism*
HIV-1 / chemistry*,  genetics
Host-Pathogen Interactions
Models, Molecular
Molecular Sequence Data
Peptide Fragments / chemistry,  genetics,  metabolism
Protein Conformation
Protein Stability
Protein Structure, Secondary
Reg. No./Substance:
0/Antigens, CD4; 0/HIV Envelope Protein gp120; 0/Ligands; 0/Peptide Fragments; 0/gp120 protein, Human immunodeficiency virus 1

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