6OTG

HIV-1 protease triple mutants V32I, I47V, V82I with GRL-011-11A (a methylamine bis-Tetrahydrofuran P2-Ligand, sulfonamide isostere derivate)

Summary for 6OTG

• Entry DOI: 10.2210/pdb6otg/pdb
• Related: 2IEN 3S54 5BRY
• Descriptor: Protease, FORMIC ACID, (3R,3aS,4R,6aR)-4-(methylamino)hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate, ... (5 entities in total)
• Functional Keywords: hiv-1 protease; antiviral inhibitors; drug resistance; x-ray crystallography, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22377.32

Authors

Wang, Y.-F.,Pawar, S.,Weber, I.T. (deposition date: 2019-05-03, release date: 2019-05-29, Last modification date: 2023-10-11)

Primary citation

Pawar, S.,Wang, Y.F.,Wong-Sam, A.,Agniswamy, J.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Structural studies of antiviral inhibitor with HIV-1 protease bearing drug resistant substitutions of V32I, I47V and V82I.
Biochem.Biophys.Res.Commun., 514:974-978, 2019

PubMed Abstract: HIV-1 protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 protease with drug resistant mutations of V32I, I47V and V82I (PR) that model the inhibitor-binding site of HIV-2 protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type protease, however, the measured inhibition constants for PR mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PR mutant in complex with inhibitor 1 at 1.5 Å resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

PubMed: 31092330
DOI: 10.1016/j.bbrc.2019.05.064

Experimental method

X-RAY DIFFRACTION (1.5 Å)