4OJR

Crystal Structure of the HIV-1 Integrase catalytic domain with GSK1264

Summary for 4OJR

• Entry DOI: 10.2210/pdb4ojr/pdb
• Descriptor: HIV-1 Integrase, (2S)-tert-butoxy[4-(8-fluoro-5-methyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl]ethanoic acid, CACODYLATE ION, ... (5 entities in total)
• Functional Keywords: viral dna integration, dna binding, ledgf binding, viral protein
• Biological source: Human immunodeficiency virus type 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): P03366
• Total number of polymer chains: 1
• Total formula weight: 18763.05

Authors

Gupta, K.,Brady, T.,Dyer, B.,Hwang, Y.,Male, F.,Nolte, R.T.,Wang, L.,Velthuisen, E.,Jeffrey, J.,Van Duyne, G.,Bushman, F.D. (deposition date: 2014-01-21, release date: 2014-06-11, Last modification date: 2024-02-28)

Primary citation

Gupta, K.,Brady, T.,Dyer, B.M.,Malani, N.,Hwang, Y.,Male, F.,Nolte, R.T.,Wang, L.,Velthuisen, E.,Jeffrey, J.,Van Duyne, G.D.,Bushman, F.D.
Allosteric Inhibition of Human Immunodeficiency Virus Integrase: LATE BLOCK DURING VIRAL REPLICATION AND ABNORMAL MULTIMERIZATION INVOLVING SPECIFIC PROTEIN DOMAINS.
J.Biol.Chem., 289:20477-20488, 2014

PubMed Abstract: HIV-1 replication in the presence of antiviral agents results in evolution of drug-resistant variants, motivating the search for additional drug classes. Here we report studies of GSK1264, which was identified as a compound that disrupts the interaction between HIV-1 integrase (IN) and the cellular factor lens epithelium-derived growth factor (LEDGF)/p75. GSK1264 displayed potent antiviral activity and was found to bind at the site occupied by LEDGF/p75 on IN by x-ray crystallography. Assays of HIV replication in the presence of GSK1264 showed only modest inhibition of the early infection steps and little effect on integration targeting, which is guided by the LEDGF/p75-IN interaction. In contrast, inhibition of late replication steps was more potent. Particle production was normal, but particles showed reduced infectivity. GSK1264 promoted aggregation of IN and preformed LEDGF/p75-IN complexes, suggesting a mechanism of inhibition. LEDGF/p75 was not displaced from IN during aggregation, indicating trapping of LEDGF/p75 in aggregates. Aggregation assays with truncated IN variants revealed that a construct with catalytic and C-terminal domains of IN only formed an open polymer associated with efficient drug-induced aggregation. These data suggest that the allosteric inhibitors of IN are promising antiviral agents and provide new information on their mechanism of action.

PubMed: 24904063
DOI: 10.1074/jbc.M114.551119

Experimental method

X-RAY DIFFRACTION (1.82 Å)