4J55

Crystal Structure of Multidrug Resistant HIV-1 Protease Clinical isolate PR20 with the potent antiviral inhibitor GRL-02031

Summary for 4J55

• Entry DOI: 10.2210/pdb4j55/pdb
• Related: 3H5B 3UCB 3UF3 3UFN 3UHL 4J54 4J5J
• Descriptor: Protease, (3aS,5R,6aR)-hexahydro-2H-cyclopenta[b]furan-5-yl [(1S,2R)-1-benzyl-2-hydroxy-3-([(4-methoxyphenyl)sulfonyl]{[(2R)-5-oxopyrrolidin-2-yl]methyl}amino)propyl]carbamate (3 entities in total)
• Functional Keywords: multidrug resistant hiv-1 protease clinical isolate pr20, clinical inhibitor amprenavir, potent antiviral inhibitor grl-0519a, potent antiviral inhibitor grl-02031, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1 (HIV-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: 22736.51

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2013-02-07, release date: 2013-05-15, Last modification date: 2023-09-20)

Primary citation

Agniswamy, J.,Shen, C.H.,Wang, Y.F.,Ghosh, A.K.,Rao, K.V.,Xu, C.X.,Sayer, J.M.,Louis, J.M.,Weber, I.T.
Extreme Multidrug Resistant HIV-1 Protease with 20 Mutations Is Resistant to Novel Protease Inhibitors with P1'-Pyrrolidinone or P2-Tris-tetrahydrofuran.
J.Med.Chem., 56:4017-4027, 2013

PubMed Abstract: Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) and GRL-0519 (3). Clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme, which is consistent with dissociation constants (KL) from isothermal titration calorimetry of 40 nM for 3, 178 nM for amprenavir, and 960 nM for 2. High resolution crystal structures of PR20-inhibitor complexes revealed altered interactions compared with the corresponding wild-type PR complexes in agreement with relative inhibition. Amprenavir lacks interactions due to PR20 mutations in the S2/S2' subsites relative to PR. Inhibitors 2 and 3 lose interactions with Arg8' in PR20 relative to the wild-type enzyme because Arg8' shifts to interact with mutated L10F side chain. Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development.

PubMed: 23590295
DOI: 10.1021/jm400231v

Experimental method

X-RAY DIFFRACTION (1.31 Å)