Title

Rationale for more diverse inhibitors in competition with substrates in HIV-1 protease

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

2010-09-08

Document Type

Article

Subjects

Anisotropy; *Binding, Competitive; Catalytic Domain; Crystallography, X-Ray; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Kinetics; Ligands; Models, Molecular; Movement; Protein Multimerization; Protein Structure, Quaternary

Disciplines

Biochemistry, Biophysics, and Structural Biology | Microbiology

Abstract

The structural fluctuations of HIV-1 protease in interaction with its substrates versus inhibitors were analyzed using the anisotropic network model. The directions of fluctuations in the most cooperative functional modes differ mainly around the dynamically key regions, i.e., the hinge axes, which appear to be more flexible in substrate complexes. The flexibility of HIV-1 protease is likely optimized for the substrates' turnover, resulting in substrate complexes being dynamic. In contrast, in an inhibitor complex, the inhibitor should bind and lock down to inactivate the active site. Protease and ligands are not independent. Substrates are also more flexible than inhibitors and have the potential to meet the dynamic distributions that are inherent in the protease. This may suggest a rationale and guidelines for designing inhibitors that can better fit the ensemble of binding sites that are dynamically accessible to the protease. reserved.

DOI of Published Version

10.1016/j.bpj.2010.06.064

Source

Biophys J. 2010 Sep 8;99(5):1650-9. Link to article on publisher's site

Journal/Book/Conference Title

Biophysical journal

Related Resources

Link to Article in PubMed

PubMed ID

20816079

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