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Crystal Structures of Novel Allosteric Peptide Inhibitors of HIV Integrase Identify New Interactions at the LEDGF Binding Site
Author(s) -
Rhodes David I.,
Peat Thomas S.,
Vandegraaff Nick,
Jeevarajah Dharshini,
Newman Janet,
Martyn John,
Coates Jonathan A. V.,
Ede Nicholas J.,
Rea Philip,
Deadman John J.
Publication year - 2011
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100350
Subject(s) - integrase , allosteric regulation , binding site , peptide , chemistry , hydrogen bond , human immunodeficiency virus (hiv) , active site , plasma protein binding , stereochemistry , enzyme , biochemistry , biology , virology , dna , molecule , organic chemistry
An optimised method of solution cyclisation gave us access to a series of peptides including SLKIDNLD ( 2 ). We investigated the crystallographic complexes of the HIV integrase (HIV‐IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding site, including hydrogen bonds with residues Thr125 and Gln95, that have not previously been described as being accessible within the binding site. We show that the peptides inhibit the interaction of lens epithelium‐derived growth factor (LEDGF) with HIV‐IN in a proximity AlphaScreen assay and in an assay for the LEDGF enhancement of HIV‐IN strand transfer. The interactions identified represent a potential framework for the development of new HIV‐IN inhibitors.