The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance

Citation
Y. Hsiou et al., The Lys103Asn mutation of HIV-1 RT: A novel mechanism of drug resistance, J MOL BIOL, 309(2), 2001, pp. 437-445
Citations number
38
Categorie Soggetti
Molecular Biology & Genetics
Journal title
JOURNAL OF MOLECULAR BIOLOGY
ISSN journal
00222836 → ACNP
Volume
309
Issue
2
Year of publication
2001
Pages
437 - 445
Database
ISI
SICI code
0022-2836(20010601)309:2<437:TLMOHR>2.0.ZU;2-D
Abstract
Inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) are widely used in the treatment of HIV infection. Loviride (an alpha -APA derivative) and HEY 097 (a quinoxaline derivative) are two potent non-nucl eoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of d rug-resistant mutants with reduced susceptibility to the inhibitors. Amino acid residue 103 in the p66 subunit of HIV-1 RT is located near a putative entrance to a hydrophobic pocket that binds NNRTIs. Substitution of asparag ine for lysine at position 103 of HIV-1 RT is associated with the developme nt of resistance to NNRTIs; this mutation contributes to clinical failure o f treatments employing NNRTIs. We have determined the structures of the unl iganded form of the Lys103Asn mutant HIV-1 RT and in complexes with lovirid e and HEY 097. The structures of wild-type and Lys103Asn mutant HIV-1 RT in complexes with NNRTIs are quite similar overall as well as in the vicinity of the bound NNRTIs. Comparison of unliganded wild-type and Lys103Asn muta nt HIV-1 RT structures reveals a network of hydrogen bonds in the Lys103Asn mutant that is not present in the wild-type enzyme. Hydrogen bonds in the unliganded Lys103Asn mutant but not in wild-type HIV-1 RT are observed betw een (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water mol ecules in the pocket and nearby pocket residues. The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could inter fere with the ability of inhibitors to bind to the enzyme. These results ar e consistent with kinetic data indicating that NNRTIs bind more slowly to L ys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mech anism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to d ifferent classes of NNRTIs. Design of NNRTIs that make favorable interactio ns with the Asn103 side-chain should be relatively effective against the Ly s103Asn drug-resistant mutant. (C) 2001 Academic Press.