3CYX

Crystal structure of HIV-1 mutant I50V and inhibitor saquinavira

Summary for 3CYX

• Entry DOI: 10.2210/pdb3cyx/pdb
• Related: 3CYW
• Related PRD ID: PRD_000454
• Descriptor: HIV-1 Protease, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide, SODIUM ION, ... (7 entities in total)
• Functional Keywords: drug resistance; hiv-1, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 22394.25

Authors

Liu, F.,Weber, I.T. (deposition date: 2008-04-27, release date: 2008-05-27, Last modification date: 2023-08-30)

Primary citation

Liu, F.,Kovalevsky, A.Y.,Tie, Y.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir.
J.Mol.Biol., 381:102-115, 2008

PubMed Abstract: HIV-1 (human immunodeficiency virus type 1) protease (PR) and its mutants are important antiviral drug targets. The PR flap region is critical for binding substrates or inhibitors and catalytic activity. Hence, mutations of flap residues frequently contribute to reduced susceptibility to PR inhibitors in drug-resistant HIV. Structural and kinetic analyses were used to investigate the role of flap residues Gly48, Ile50, and Ile54 in the development of drug resistance. The crystal structures of flap mutants PR(I50V) (PR with I50V mutation), PR(I54V) (PR with I54V mutation), and PR(I54M) (PR with I54M mutation) complexed with saquinavir (SQV) as well as PR(G48V) (PR with G48V mutation), PR(I54V), and PR(I54M) complexed with darunavir (DRV) were determined at resolutions of 1.05-1.40 A. The PR mutants showed changes in flap conformation, interactions with adjacent residues, inhibitor binding, and the conformation of the 80s loop relative to the wild-type PR. The PR contacts with DRV were closer in PR(G48V)-DRV than in the wild-type PR-DRV, whereas they were longer in PR(I54M)-DRV. The relative inhibition of PR(I54V) and that of PR(I54M) were similar for SQV and DRV. PR(G48V) was about twofold less susceptible to SQV than to DRV, whereas the opposite was observed for PR(I50V). The observed inhibition was in agreement with the association of G48V and I50V with clinical resistance to SQV and DRV, respectively. This analysis of structural and kinetic effects of the mutants will assist in the development of more effective inhibitors for drug-resistant HIV.

PubMed: 18597780
DOI: 10.1016/j.jmb.2008.05.062

Experimental method

X-RAY DIFFRACTION (1.2 Å)