Document Detail


Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance.
MedLine Citation:
PMID:  21030679     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding of viral resistance to these molecules have been hampered by a paucity of available structural data. We recently reported cocrystal structures of the prototype foamy virus (PFV) intasome with raltegravir and elvitegravir, establishing the general INSTI binding mode. We now present an expanded set of cocrystal structures containing PFV intasomes complexed with first- and second-generation INSTIs at resolutions of up to 2.5 Å. Importantly, the improved resolution allowed us to refine the complete coordination spheres of the catalytic metal cations within the INSTI-bound intasome active site. We show that like the Q148H/G140S and N155H HIV-1 IN variants, the analogous S217H and N224H PFV INs display reduced sensitivity to raltegravir in vitro. Crystal structures of the mutant PFV intasomes in INSTI-free and -bound forms revealed that the amino acid substitutions necessitate considerable conformational rearrangements within the IN active site to accommodate an INSTI, thus explaining their adverse effects on raltegravir antiviral activity. Furthermore, our structures predict physical proximity and an interaction between HIV-1 IN mutant residues His148 and Ser/Ala140, rationalizing the coevolution of Q148H and G140S/A mutations in drug-resistant viral strains.
Authors:
Stephen Hare; Ann M Vos; Reginald F Clayton; Jan W Thuring; Maxwell D Cummings; Peter Cherepanov
Related Documents :
17360759 - Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 prot...
18691029 - Response of feline immunodeficiency virus (fiv) to tipranavir may provide new clues for...
15482949 - Discovery of potent pyrrolidone-based hiv-1 protease inhibitors with enhanced drug-like...
8144659 - In vitro characterization of nonpeptide irreversible inhibitors of hiv proteases.
2548279 - Conserved folding in retroviral proteases: crystal structure of a synthetic hiv-1 prote...
9195919 - A metal-induced conformational change and activation of hiv-1 integrase.
6185429 - Characterization of a galactose-specific lectin from actinomyces viscosus by a model ag...
19194479 - Spink9: a selective, skin-specific kazal-type serine protease inhibitor.
12437139 - Foldase function of the cathepsin s proregion is strictly based upon its domain structure.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-28
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-18     Completed Date:  2010-12-21     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20057-62     Citation Subset:  IM    
Affiliation:
Division of Infectious Diseases, Imperial College London, London W2 1PG, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
PDB/3OY9;  3OYA;  3OYB;  3OYC;  3OYD;  3OYE;  3OYF;  3OYG;  3OYH;  3OYI;  3OYJ;  3OYK;  3OYL;  3OYM;  3OYN
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution / genetics
Catalytic Domain
Drug Resistance, Viral / genetics*
Evolution, Molecular*
HIV Integrase Inhibitors / chemistry,  metabolism,  pharmacology*
HIV-1 / enzymology,  genetics
Inhibitory Concentration 50
Integrases / metabolism*
Mutation / genetics
Pyrrolidinones / chemistry,  pharmacology
Retroviridae / enzymology*
Grant Support
ID/Acronym/Agency:
G0900116//Medical Research Council
Chemical
Reg. No./Substance:
0/HIV Integrase Inhibitors; 0/Pyrrolidinones; 22VKV8053U/raltegravir; EC 2.7.7.-/Integrases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics.
Next Document:  A biochemical mechanism for the oncogenic potential of the p110beta catalytic subunit of phosphoinos...