4JLH

HIV-1 Integrase Catalytic Core Domain A128T Mutant Complexed with Allosteric Inhibitor

Summary for 4JLH

• Entry DOI: 10.2210/pdb4jlh/pdb
• Related: 1ITG
• Descriptor: HIV-1 Integrase catalytic core domain, (2S)-[6-bromo-4-(4-chlorophenyl)-2-methylquinolin-3-yl](methoxy)ethanoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: integrase, ccd, dde motif, drug resistance, a128t mutation, dimer interface, allosteric inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-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 : P12497
• Total number of polymer chains: 1
• Total formula weight: 18699.22

Authors

Feng, L.,Kvaratskhelia, M. (deposition date: 2013-03-12, release date: 2013-05-01, Last modification date: 2024-11-06)

Primary citation

Feng, L.,Sharma, A.,Slaughter, A.,Jena, N.,Koh, Y.,Shkriabai, N.,Larue, R.C.,Patel, P.A.,Mitsuya, H.,Kessl, J.J.,Engelman, A.,Fuchs, J.R.,Kvaratskhelia, M.
The A128T Resistance Mutation Reveals Aberrant Protein Multimerization as the Primary Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors.
J.Biol.Chem., 288:15813-15820, 2013

PubMed Abstract: Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a very promising new class of anti-HIV-1 agents that exhibit a multimodal mechanism of action by allosterically modulating IN multimerization and interfering with IN-lens epithelium-derived growth factor (LEDGF)/p75 binding. Selection of viral strains under ALLINI pressure has revealed an A128T substitution in HIV-1 IN as a primary mechanism of resistance. Here, we elucidated the structural and mechanistic basis for this resistance. The A128T substitution did not affect the hydrogen bonding between ALLINI and IN that mimics the IN-LEDGF/p75 interaction but instead altered the positioning of the inhibitor at the IN dimer interface. Consequently, the A128T substitution had only a minor effect on the ALLINI IC50 values for IN-LEDGF/p75 binding. Instead, ALLINIs markedly altered the multimerization of IN by promoting aberrant higher order WT (but not A128T) IN oligomers. Accordingly, WT IN catalytic activities and HIV-1 replication were potently inhibited by ALLINIs, whereas the A128T substitution in IN resulted in significant resistance to the inhibitors both in vitro and in cell culture assays. The differential multimerization of WT and A128T INs induced by ALLINIs correlated with the differences in infectivity of HIV-1 progeny virions. We conclude that ALLINIs primarily target IN multimerization rather than IN-LEDGF/p75 binding. Our findings provide the structural foundations for developing improved ALLINIs with increased potency and decreased potential to select for drug resistance.

PubMed: 23615903
DOI: 10.1074/jbc.M112.443390

Experimental method

X-RAY DIFFRACTION (2.09 Å)