Document Detail


Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening.
MedLine Citation:
PMID:  23342998     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.
Authors:
Joseph D Bauman; Disha Patel; Chhaya Dharia; Marc W Fromer; Sameer Ahmed; Yulia Frenkel; R S K Vijayan; J Thomas Eck; William C Ho; Kalyan Das; Aaron J Shatkin; Eddy Arnold
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-20
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-11     Completed Date:  2013-06-11     Revised Date:  2014-04-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2738-46     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
PDB/4I7G;  4ICL;  4ID4;  4IDK;  4IFV;  4IFY;  4IG0;  4IG3
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MeSH Terms
Descriptor/Qualifier:
Allosteric Site
Base Sequence
Crystallography, X-Ray
DNA Primers
HIV Reverse Transcriptase / chemistry,  metabolism*
Models, Molecular
Protein Conformation
Grant Support
ID/Acronym/Agency:
AI27690/AI/NIAID NIH HHS; P41 GM103485/GM/NIGMS NIH HHS; P50 GM103368/GM/NIGMS NIH HHS; R37 AI027690/AI/NIAID NIH HHS; RR-01646/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; EC 2.7.7.-/reverse transcriptase, Human immunodeficiency virus 1; EC 2.7.7.49/HIV Reverse Transcriptase
Comments/Corrections

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


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