1HQE

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1

Summary for 1HQE

• Entry DOI: 10.2210/pdb1hqe/pdb
• Related: 1HPZ 1HQU
• Descriptor: POL POLYPROTEIN (3 entities in total)
• Functional Keywords: nucleotidyltransferase, transferase
• Biological source: Human immunodeficiency virus 1; More
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 114752.57

Authors

Ding, J.,Hsiou, Y.,Arnold, E. (deposition date: 2000-12-15, release date: 2001-05-30, Last modification date: 2023-08-09)

Primary citation

Hsiou, Y.,Ding, J.,Das, K.,Clark Jr., A.D.,Boyer, P.L.,Lewi, P.,Janssen, P.A.,Kleim, J.P.,Rosner, M.,Hughes, S.H.,Arnold, E.
The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.
J.Mol.Biol., 309:437-445, 2001

PubMed 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 HBY 097 (a quinoxaline derivative) are two potent non-nucleoside RT inhibitors (NNRTIs) that have been used in human clinical trials. A major problem for existing anti-retroviral therapy is the emergence of drug-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 asparagine for lysine at position 103 of HIV-1 RT is associated with the development of resistance to NNRTIs; this mutation contributes to clinical failure of treatments employing NNRTIs. We have determined the structures of the unliganded form of the Lys103Asn mutant HIV-1 RT and in complexes with loviride and HBY 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 mutant 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 between (1) the side-chains of Asn103 and Tyr188 and (2) well-ordered water molecules 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 interfere with the ability of inhibitors to bind to the enzyme. These results are consistent with kinetic data indicating that NNRTIs bind more slowly to Lys103Asn mutant than to wild-type HIV-1 RT. This novel drug-resistance mechanism explains the broad cross-resistance of Lys103Asn mutant HIV-1 RT to different classes of NNRTIs. Design of NNRTIs that make favorable interactions with the Asn103 side-chain should be relatively effective against the Lys103Asn drug-resistant mutant.

PubMed: 11371163
DOI: 10.1006/jmbi.2001.4648

Experimental method

X-RAY DIFFRACTION (2.7 Å)