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Similarities in the HIV‐1 and ASV integrase active sites upon metal cofactor binding
Author(s) -
Lins Roberto D.,
Straatsma T. P.,
Briggs James M.
Publication year - 2000
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/(sici)1097-0282(20000405)53:4<308::aid-bip3>3.0.co;2-h
Subject(s) - integrase , chemistry , integrases , active site , reverse transcriptase , stereochemistry , divalent , dna , binding site , hiv 1 protease , enzyme , crystallography , protease , biochemistry , rna , organic chemistry , gene
The HIV‐1 integrase, which is essential for viral replication, catalyzes the insertion of viral DNA into the host chromosome thereby recruiting host cell machinery into making viral proteins. It represents the third main HIV enzyme target for inhibitor design, the first two being the reverse transcriptase and the protease. We report here a fully hydrated 2 ns molecular dynamics simulation performed using parallel NWChem3.2.1 with the AMBER95 force field. The HIV‐1 integrase catalytic domain previously determined by crystallography (1B9D) and modeling including two Mg 2+ ions placed into the active site based on an alignment against an ASV integrase structure containing two divalent metals (1VSH), was used as the starting structure. The simulation reveals a high degree of flexibility in the region of residues 140–149 even in the presence of a second divalent metal ion and a dramatic conformational change of the side chain of E152 when the second metal ion is present. This study shows similarities in the behavior of the catalytic residues in the HIV‐1 and ASV integrases upon metal binding. The present simulation also provides support to the hypothesis that the second metal ion is likely to be carried into the HIV‐1 integrase active site by the substrate, a strand of DNA. © 2000 John Wiley & Sons, Inc. Biopoly 53: 308–315, 2000