2F81

HIV-1 Protease mutant L90M complexed with inhibitor TMC114

Summary for 2F81

• Entry DOI: 10.2210/pdb2f81/pdb
• Related: 2F80 2F8G
• Descriptor: POL POLYPROTEIN, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: hiv-1 protease-inhibitor complex, hydrolase
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P04587
• Total number of polymer chains: 2
• Total formula weight: 22343.18

Authors

Kovalevsky, A.Y.,Weber, I.T. (deposition date: 2005-12-01, release date: 2006-03-07, Last modification date: 2024-02-14)

Primary citation

Kovalevsky, A.Y.,Tie, Y.,Liu, F.,Boross, P.I.,Wang, Y.F.,Leshchenko, S.,Ghosh, A.K.,Harrison, R.W.,Weber, I.T.
Effectiveness of Nonpeptide Clinical Inhibitor TMC-114 on HIV-1 Protease with Highly Drug Resistant Mutations D30N, I50V, and L90M.
J.Med.Chem., 49:1379-1387, 2006

PubMed Abstract: The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.

PubMed: 16480273
DOI: 10.1021/jm050943c

Experimental method

X-RAY DIFFRACTION (1.25 Å)