2HS1

Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor

Summary for 2HS1

• Entry DOI: 10.2210/pdb2hs1/pdb
• Descriptor: HIV-1 Protease, CHLORIDE ION, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, ... (5 entities in total)
• Functional Keywords: ultra-high resolution active site surface binding site, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22789.23

Authors

Weber, I.T.,Kovalevsky, A.Y. (deposition date: 2006-07-20, release date: 2006-10-03, Last modification date: 2024-02-14)

Primary citation

Kovalevsky, A.Y.,Liu, F.,Leshchenko, S.,Ghosh, A.K.,Louis, J.M.,Harrison, R.W.,Weber, I.T.
Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114.
J.Mol.Biol., 363:161-173, 2006

PubMed Abstract: 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.

PubMed: 16962136
DOI: 10.1016/j.jmb.2006.08.007

Experimental method

X-RAY DIFFRACTION (0.84 Å)