2G69

Structure of Unliganded HIV-1 Protease F53L Mutant

Summary for 2G69

• Entry DOI: 10.2210/pdb2g69/pdb
• Descriptor: protease (2 entities in total)
• Functional Keywords: aspartic protease, catalysis, unliganded, flap mutant, non-active site mutant, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 10706.66

Authors

Kovalevsky, A.Y.,Liu, F. (deposition date: 2006-02-24, release date: 2006-05-09, Last modification date: 2024-02-14)

Primary citation

Liu, F.,Kovalevsky, A.Y.,Louis, J.M.,Boross, P.I.,Wang, Y.F.,Harrison, R.W.,Weber, I.T.
Mechanism of Drug Resistance Revealed by the Crystal Structure of the Unliganded HIV-1 Protease with F53L Mutation.
J.Mol.Biol., 358:1191-1199, 2006

PubMed Abstract: Mutations 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.

PubMed: 16569415
DOI: 10.1016/j.jmb.2006.02.076

Experimental method

X-RAY DIFFRACTION (1.35 Å)