University of Massachusetts Medical School Faculty Publications

Title

Modulation of HIV protease flexibility by the T80N mutation

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

12-9-2014

Document Type

Article

Disciplines

Biochemistry | Molecular Biology | Structural Biology

Abstract

The flexibility of HIV protease plays a critical role in enabling enzymatic activity and is required for substrate access to the active site. While the importance of flexibility in the flaps that cover the active site is well known, flexibility in other parts of the enzyme is also critical for function. One key region is a loop containing Thr 80 which forms the walls of the active site. Although not situated within the active site, amino acid Thr80 is absolutely conserved. The mutation T80N preserves the structure of the enzyme but catalytic activity is completely lost. To investigate the potential influence of the T80N mutation on HIVp flexibility, wide-angle scattering (WAXS) data was measured for a series of HIV protease variants. Starting with a calculated WAXS pattern from a rigid atomic model, the modulations in the intensity distribution caused by structural fluctuations in the protein were predicted by simple analytic methods and compared to the experimental data. An analysis of T80N WAXS data shows that this variant is significantly more rigid than the WT across all length scales. The effects of this single point mutation extend throughout the protein, so as to alter the mobility of amino acids in the enzymatic core. These results support the contentions that significant protein flexibility extends throughout HIV protease and is critical to catalytic function.

Rights and Permissions

Citation: Proteins. 2014 Dec 9. doi: 10.1002/prot.24737. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Proteins

PubMed ID

25488402