2Z4O

Wild Type HIV-1 Protease with potent Antiviral inhibitor GRL-98065

Summary for 2Z4O

• Entry DOI: 10.2210/pdb2z4o/pdb
• Related: 2QCI 2QD6 2QD7 2QD8
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: hiv-1, wild type protease, protease inhibitor, hydrolase
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• Total number of polymer chains: 2
• Total formula weight: 22210.95

Authors

Wang, Y.F.,Tie, Y.,Boross, P.I.,Tozser, J.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T. (deposition date: 2007-06-20, release date: 2008-04-22, Last modification date: 2023-11-01)

Primary citation

Wang, Y.F.,Tie, Y.,Boross, P.I.,Tozser, J.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease.
J.Med.Chem., 50:4509-4515, 2007

PubMed 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.

PubMed: 17696515
DOI: 10.1021/jm070482q

Experimental method

X-RAY DIFFRACTION (1.6 Å)