1HVS

STRUCTURAL BASIS OF DRUG RESISTANCE FOR THE V82A MUTANT OF HIV-1 PROTEASE: BACKBONE FLEXIBILITY AND SUBSITE REPACKING

Summary for 1HVS

• Entry DOI: 10.2210/pdb1hvs/pdb
• Descriptor: HIV-1 PROTEASE, N-{1-BENZYL-(2R,3S)-2,3-DIHYDROXY-4-[3-METHYL-2-(3-METHYL-3-PYRIDIN-2-YLMETHYL-UREIDO)-BUTYRYLAMINO]-5-PHENYL-PENTYL}-3-METHYL-2-(3-METHYL-3-PYRIDIN-2-YLMETHYL-UREIDO)-BUTYRAMIDE (2 entities in total)
• Functional Keywords: hydrolase (acid protease)
• Biological source: Human immunodeficiency virus 1
• 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): P04587
• Total number of polymer chains: 2
• Total formula weight: 22346.38

Authors

Baldwin, E.T.,Bhat, T.N.,Liu, B.,Pattabiraman, N.,Erickson, J.W. (deposition date: 1994-11-17, release date: 1995-02-14, Last modification date: 2024-02-07)

Primary citation

Baldwin, E.T.,Bhat, T.N.,Liu, B.,Pattabiraman, N.,Erickson, J.W.
Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase.
Nat.Struct.Biol., 2:244-249, 1995

PubMed Abstract: A major problem in the development of antiviral therapies for AIDS has been the emergence of drug resistance. We report an analysis of the structure of a Val 82 to Ala mutant of HIV-1 proteinase complexed to A-77003, a C2 symmetry-based inhibitor. Modelling studies predicted that the V82A mutation would result in decreased van der Waals' interactions with the phenyl rings of A-77003 in both S1 and S1' subsites. Unexpected rearrangements of the protein backbone, however, resulted in favourable re-packing of inhibitor and enzyme atoms in the S1 but not the S1' subsite. This analysis reveals the importance of enzyme flexibility in accommodating alternate packing arrangements, and can be applied to the re-design of inhibitors targeted to drug resistant variants which emerge in the clinic.

PubMed: 7773792
DOI: 10.1038/nsb0395-244

Experimental method

X-RAY DIFFRACTION (2.25 Å)