6DIL

HIV-1 protease with single mutation L76V in complex with tipranavir

Summary for 6DIL

• Entry DOI: 10.2210/pdb6dil/pdb
• Related: 6DIF 6DJ1 6DJ2
• Descriptor: HIV-1 protease, SODIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: antiviral agents, protein-inhibitor structures, hiv drug resistance, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22485.19

Authors

Wong-Sam, A.E.,Wang, Y.-F.,Weber, I.T. (deposition date: 2018-05-23, release date: 2018-10-17, Last modification date: 2023-10-11)

Primary citation

Wong-Sam, A.,Wang, Y.F.,Zhang, Y.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.
ACS Omega, 3:12132-12140, 2018

PubMed Abstract: Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds and , were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PR). Compound exhibited the best value of 1.9 nM for PR, whereas the other three inhibitors had values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PR compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PR were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.

PubMed: 30288468
DOI: 10.1021/acsomega.8b01683

Experimental method

X-RAY DIFFRACTION (1.482 Å)