2hs1
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(New page: 200px<br /> <applet load="2hs1" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hs1, resolution 0.84Å" /> '''Ultra-high resoluti...)
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Revision as of 12:44, 8 November 2007
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Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor
Overview
TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease, (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high, 0.84 A resolution crystal structure of the TMC114 complex with PR, containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A, resolution structure of a complex with PR(M46L). These structures show, TMC114 bound at two distinct sites, one in the active-site cavity and the, second on the surface of one of the flexible flaps in the PR dimer., Remarkably, TMC114 binds at these two sites simultaneously in two, diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the, S-enantiomeric nitrogen rather than the one with the R-enantiomeric, nitrogen. The existence of the second binding site and two diastereomers, suggest a mechanism for the high effectiveness of TMC114 on drug-resistant, HIV and the potential design of new inhibitors.
About this Structure
2HS1 is a Single protein structure of sequence from Human immunodeficiency virus 1 with CL, 017 and DMS as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114., Kovalevsky AY, Liu F, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2006 Oct 13;363(1):161-73. Epub 2006 Aug 4. PMID:16962136
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