2QD6: Hiv-1 Protease Mutant I50v With Potent Antiviral Inhibitor Grl-98065

Citation:
Abstract
The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A, and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PR(D30N), PR(I50V), PR(V82A), and PR(I84V) relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PR(D30N), where inhibitor 1 was approximately 3-fold less potent. The high resolution (1.11-1.60 Angstrom) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PR(D30N) and PR(V82A) showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PR(I50V) and PR(I84V). Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.
PDB ID: 2QD6Download
MMDB ID: 63914
PDB Deposition Date: 2007/6/20
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 1.28  Å
Source Organism:
Similar Structures:
Biological Unit for 2QD6: dimeric; determined by author and by software (PISA)
Molecular Components in 2QD6
Label Count Molecule
Proteins (2 molecules)
2
Protease
Molecule annotation
Chemicals (6 molecules)
1
1
2
2
3
2
4
1
* Click molecule labels to explore molecular sequence information.

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