3OXX

Crystal Structure of HIV-1 I50V, A71V Protease in Complex with the Protease Inhibitor Atazanavir

Summary for 3OXX

• Entry DOI: 10.2210/pdb3oxx/pdb
• Related: 3OXV 3OXW 3OY4
• Descriptor: HIV-1 PROTEASE, GLYCEROL, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: hiv-1 protease, inhibitor resistance, aids, aspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: HIV-1 M:B_ARV2/SF2 (HIV-1)
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03369
• Total number of polymer chains: 4
• Total formula weight: 45860.87

Authors

Schiffer, C.A.,Bandaranayake, R.M. (deposition date: 2010-09-22, release date: 2011-09-28, Last modification date: 2023-09-06)

Primary citation

Mittal, S.,Bandaranayake, R.M.,King, N.M.,Prabu-Jeyabalan, M.,Nalam, M.N.,Nalivaika, E.A.,Yilmaz, N.K.,Schiffer, C.A.
Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50.
J.Virol., 87:4176-4184, 2013

PubMed Abstract: Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions.

PubMed: 23365446
DOI: 10.1128/JVI.03486-12

Experimental method

X-RAY DIFFRACTION (1.65 Å)