Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50
Authors
Mittal, SeemaBandaranayake, Rajintha M.
King, Nancy M.
Prabu-Jeyabalan, Moses
Nalam, Madhavi N. L.
Nalivaika, Ellen A.
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2013-04-01Keywords
Anti-HIV AgentsCarbamates
Crystallography, X-Ray
*Drug Resistance, Viral
HIV Protease
HIV-1
Humans
Kinetics
Models, Molecular
Mutant Proteins
*Mutation, Missense
Oligopeptides
Point Mutation
Protein Binding
Protein Conformation
Pyridines
Sulfonamides
Thermodynamics
Biochemistry, Biophysics, and Structural Biology
Chemicals and Drugs
Immunology and Infectious Disease
Infectious Disease
Virology
Virus Diseases
Metadata
Show full item recordAbstract
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.Source
J Virol. 2013 Apr;87(8):4176-84. doi: 10.1128/JVI.03486-12. Epub 2013 Jan 30. Link to article on publisher's siteDOI
10.1128/JVI.03486-12Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28942PubMed ID
23365446Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1128/JVI.03486-12