Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope
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UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2011-07-19Keywords
Amino Acid SequenceConserved Sequence
Crystallography, X-Ray
Drug Resistance, Viral
HIV Protease
HIV-1
Humans
Hydrogen Bonding
Molecular Dynamics Simulation
Molecular Sequence Data
Mutation
Substrate Specificity
Molecular Biology
Virology
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Show full item recordAbstract
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate envelope, because these regions are crucial for drug binding but not for substrate recognition. We extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. We simulated the molecular dynamics of seven PR-substrate complexes to estimate the conformational flexibility of the bound substrates. Interdependence of substrate-protease interactions might compensate for variations in cleavage-site sequences and explain how a diverse set of sequences are recognized as substrates by the same enzyme. This diversity might be essential for regulating sequential processing of substrates. We define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance.Source
J Mol Biol. 2011 Jul 22;410(4):726-44. Link to article on publisher's siteDOI
10.1016/j.jmb.2011.03.053Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26003PubMed ID
21762811Notes
Co-author Aysegul Ozen is a student in the Biochemistry & Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.jmb.2011.03.053