2p3a
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Crystal Structure of the multi-drug resistant mutant subtype B HIV protease complexed with TL-3 inhibitor
OverviewOverview
Although a majority of HIV-1 infections in Brazil are caused by the, subtype B virus (also prevalent in the United States and Western Europe), viral subtypes F and C are also found very frequently. Genomic differences, between the subtypes give rise to sequence variations in the encoded, proteins, including the HIV-1 protease. The current anti-HIV drugs have, been developed primarily against subtype B and the effects arising from, the combination of drug-resistance mutations with the naturally existing, polymorphisms in non-B HIV-1 subtypes are only beginning to be elucidated., To gain more insights into the structure and function of different, variants of HIV proteases, we have determined a 2.1 A structure of the, native subtype F HIV-1 protease (PR) in complex with the protease, inhibitor TL-3. We have also solved crystal structures of two multi-drug, resistant mutant HIV PRs in complex with TL-3, from subtype B (Bmut), carrying the primary mutations V82A and L90M, and from subtype F (Fmut), carrying the primary mutation V82A plus the secondary mutation M36I, at, 1.75 A and 2.8 A resolution, respectively. The proteases Bmut, Fwt and, Fmut exhibit sevenfold, threefold, and 54-fold resistance to TL-3, respectively. In addition, the structure of subtype B wild type HIV-PR in, complex with TL-3 has been redetermined in space group P6(1), consistent, with the other three structures. Our results show that the primary, mutation V82A causes the known effect of collapsing the S1/S1' pockets, that ultimately lead to the reduced inhibitory effect of TL-3. Our results, further indicate that two naturally occurring polymorphic substitutions in, subtype F and other non-B HIV proteases, M36I and L89M, may lead to early, development of drug resistance in patients infected with non-B HIV, subtypes.
About this StructureAbout this Structure
2P3A is a Protein complex structure of sequences from Human immunodeficiency virus 1 with 3TL as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development., Sanches M, Krauchenco S, Martins NH, Gustchina A, Wlodawer A, Polikarpov I, J Mol Biol. 2007 Jun 15;369(4):1029-40. Epub 2007 Mar 24. PMID:17467738
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