BACKGROUND: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors. RESULTS: We report here crystal structures at up to 1.7 A resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the flap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. CONCLUSIONS: This study shows that besides the residues in the flap and residues 79-81 in the S1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.
BACKGROUND: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors. RESULTS: We report here crystal structures at up to 1.7 A resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the flap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. CONCLUSIONS: This study shows that besides the residues in the flap and residues 79-81 in the S1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.
Authors: D Lamarre; G Croteau; E Wardrop; L Bourgon; D Thibeault; C Clouette; M Vaillancourt; E Cohen; C Pargellis; C Yoakim; P C Anderson Journal: Antimicrob Agents Chemother Date: 1997-05 Impact factor: 5.191
Authors: Péter Bagossi; Tamás Sperka; Anita Fehér; János Kádas; Gábor Zahuczky; Gabriella Miklóssy; Péter Boross; József Tözsér Journal: J Virol Date: 2005-04 Impact factor: 5.103
Authors: Mi Li; Gary S Laco; Mariusz Jaskolski; Jan Rozycki; Jerry Alexandratos; Alexander Wlodawer; Alla Gustchina Journal: Proc Natl Acad Sci U S A Date: 2005-12-13 Impact factor: 11.205
Authors: H L Sham; D J Kempf; A Molla; K C Marsh; G N Kumar; C M Chen; W Kati; K Stewart; R Lal; A Hsu; D Betebenner; M Korneyeva; S Vasavanonda; E McDonald; A Saldivar; N Wideburg; X Chen; P Niu; C Park; V Jayanti; B Grabowski; G R Granneman; E Sun; A J Japour; J M Leonard; J J Plattner; D W Norbeck Journal: Antimicrob Agents Chemother Date: 1998-12 Impact factor: 5.191