1HVS

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

1HVS の概要

• エントリーDOI: 10.2210/pdb1hvs/pdb
• 分子名称: 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)
• 機能のキーワード: hydrolase (acid protease)
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: 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
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22346.38

構造登録者

Baldwin, E.T.,Bhat, T.N.,Liu, B.,Pattabiraman, N.,Erickson, J.W. (登録日: 1994-11-17, 公開日: 1995-02-14, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.25 Å)