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
PubMed ID
20816079
Repository Citation
Ozer N, Schiffer CA, Haliloglu T. (2010). Rationale for more diverse inhibitors in competition with substrates in HIV-1 protease. Biochemistry and Molecular Biotechnology Publications. https://doi.org/10.1016/j.bpj.2010.06.064. Retrieved from https://escholarship.umassmed.edu/bmp_pp/141