2g69
Structure of Unliganded HIV-1 Protease F53L MutantStructure of Unliganded HIV-1 Protease F53L Mutant
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PR(F53L) showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PR(F53L) was determined in the unliganded form at 1.35 Angstrom resolution in space group P4(1)2(1)2. The tips of the flaps in PR(F53L) had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50'. The changes in interactions between the flaps agreed with the reduced stability of PR(F53L) relative to wild-type PR. The altered flap interactions in the unliganded form of PR(F53L) suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants. Mechanism of drug resistance revealed by the crystal structure of the unliganded HIV-1 protease with F53L mutation.,Liu F, Kovalevsky AY, Louis JM, Boross PI, Wang YF, Harrison RW, Weber IT J Mol Biol. 2006 May 19;358(5):1191-9. Epub 2006 Mar 20. PMID:16569415[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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