2P3D

Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor

Summary for 2P3D

• Entry DOI: 10.2210/pdb2p3d/pdb
• Related: 2P3A 2P3B 2P3C
• Related PRD ID: PRD_000434
• Descriptor: Pol protein, benzyl [(1S,4S,7S,8R,9R,10S,13S,16S)-7,10-dibenzyl-8,9-dihydroxy-1,16-dimethyl-4,13-bis(1-methylethyl)-2,5,12,15,18-pentaoxo-20-phenyl-19-oxa-3,6,11,14,17-pentaazaicos-1-yl]carbamate (3 entities in total)
• Functional Keywords: multi-drug resistant mutant subtype f hiv protease, tl-3 inhibitor, non-b hiv protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22634.60

Authors

Sanches, M.,Krauchenco, S.,Martins, N.H.,Gustchina, A.,Wlodawer, A.,Polikarpov, I. (deposition date: 2007-03-08, release date: 2007-04-24, Last modification date: 2024-04-03)

Primary citation

Sanches, M.,Krauchenco, S.,Martins, N.H.,Gustchina, A.,Wlodawer, A.,Polikarpov, I.
Structural Characterization of B and non-B Subtypes of HIV-Protease: Insights into the Natural Susceptibility to Drug Resistance Development.
J.Mol.Biol., 369:1029-1040, 2007

PubMed Abstract: 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.

PubMed: 17467738
DOI: 10.1016/j.jmb.2007.03.049

Experimental method

X-RAY DIFFRACTION (2.8 Å)