Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 116, Issue 49, Pages 14235-14244Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp308207h
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Funding
- NSF [MBC-0746533]
- NIH [R37 AI28571]
- UF Center for AIDS Research
- NHMFL-IHRP
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [746533] Funding Source: National Science Foundation
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Double electron-electron resonance (DEER) spectroscopy was utilized to investigate shifts in conformational sampling induced by nine FDA-approved protease inhibitors (PIs) and a nonhydrolyzable substrate mimic for human immunodeficiency virus type 1 protease (HIV-1 PR) subtype B, subtype C, and CRF_01 A/E. The ligand-bound subtype C protease has broader DEER distance profiles, but trends for inhibitor-induced conformational shifts are comparable to those previously reported for subtype B. Ritonavir, one of the strong-binding inhibitors for subtypes B and C, induces less of the closed conformation in CRF_01 A/E. H-1-N-15 heteronuclear single-quantum coherence (HSQC) spectra were acquired for each protease construct titrated with the same set of inhibitors. NMR H-1-N-15 HSQC titration data show that inhibitor residence time in the protein binding pocket, inferred from resonance exchange broadening, shifting or splitting correlates with the degree of ligand-induced flap closure measured by DEER spectroscopy. These parallel results show that the ligand-induced conformational shifts resulting from protein-ligand interactions characterized by DEER spectroscopy of HIV-1 PR obtained at the cryogenic temperature are consistent with more physiological solution protein ligand interactions observed by solution NMR spectroscopy.
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