Format

Send to

Choose Destination
J Struct Biol. 2013 Nov;184(2):245-50. doi: 10.1016/j.jsb.2013.07.008. Epub 2013 Jul 25.

Reduced HIV-1 integrase flexibility as a mechanism for raltegravir resistance.

Author information

1
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

HIV-1 integrase is an essential enzyme necessary for the replication of the HIV virus as it catalyzes the insertion of the viral genome into the host chromosome. Raltegravir was the first integrase inhibitor approved by the FDA for antiretroviral treatment. HIV patients on raltegravir containing regimens often develop drug resistance mutations at residue 140 and 148 in the catalytic 140's loop resulting in a 5-10 fold decrease in susceptibility to raltegravir. Obtaining crystallographic structure information on the Q148H/R, G140S/A primary and secondary mutations has been elusive. Using 10 ns molecular dynamics simulations, we present a detailed analysis of the structural changes induced by these mutations. The formation frequency of a transient helix in the catalytic 140's loop is increased and the length of this helix is extended from 3-residues to 4 in the mutants relative to the wild type. This helix causes reduced flexibility in the protein active site and therefore serves as a gating mechanism restricting the access of raltegravir to the integrase binding pocket. These results suggest that resistance to raltegravir occurs through a common mechanism of altering the formation frequency of transient secondary structures such as α2 and β5 in addition to the conformational changes in the 140's loop therefore decreasing the flexibility of the HIV-1 integrase protein. The reduced integrase flexibility serves as a mechanism of resistance to raltegravir.

KEYWORDS:

Drug resistance; HIV-1 integrase; Molecular dynamics; NAMD; Raltegravir

PMID:
23891838
DOI:
10.1016/j.jsb.2013.07.008
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center