5JL4

Inhibitor resistant mutant catalytic core domain of HIV-1 Integrase

Summary for 5JL4

• Entry DOI: 10.2210/pdb5jl4/pdb
• Descriptor: Integrase, SULFATE ION (3 entities in total)
• Functional Keywords: allini hiv integrase multimerization, dna binding protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 36287.37

Authors

Feng, L.,Kobe, M.,Kvaratskhelia, M. (deposition date: 2016-04-26, release date: 2017-10-04, Last modification date: 2023-09-27)

Primary citation

Hoyte, A.C.,Jamin, A.V.,Koneru, P.C.,Kobe, M.J.,Larue, R.C.,Fuchs, J.R.,Engelman, A.N.,Kvaratskhelia, M.
Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing.
J. Biol. Chem., 292:19814-19825, 2017

PubMed Abstract: The pyridine-based multimerization selective HIV-1 integrase (IN) inhibitors (MINIs) are a distinct subclass of allosteric IN inhibitors. MINIs potently inhibit HIV-1 replication during virion maturation by inducing hyper- or aberrant IN multimerization but are largely ineffective during the early steps of viral replication. Here, we investigated the mechanism for the evolution of a triple IN substitution (T124N/V165I/T174I) that emerges in cell culture with a representative MINI, KF116. We show that HIV-1 NL4-3(IN T124N/V165I/T174I) confers marked (>2000-fold) resistance to KF116. Two IN substitutions (T124N/T174I) directly weaken inhibitor binding at the dimer interface of the catalytic core domain but at the same time markedly impair HIV-1 replication capacity. Unexpectedly, T124N/T174I IN substitutions inhibited proteolytic processing of HIV-1 polyproteins Gag and Gag-Pol, resulting in immature virions. Strikingly, the addition of the third IN substitution (V165I) restored polyprotein processing, virus particle maturation, and significant levels of replication capacity. These results reveal an unanticipated role of IN for polyprotein proteolytic processing during virion morphogenesis. The complex evolutionary pathway for the emergence of resistant viruses, which includes the need for the compensatory V165I IN substitution, highlights a relatively high genetic barrier exerted by MINI KF116. Additionally, we have solved the X-ray structure of the drug-resistant catalytic core domain protein, which provides means for rational development of second-generation MINIs.

PubMed: 28972144
DOI: 10.1074/jbc.M117.816645

Experimental method

X-RAY DIFFRACTION (1.758 Å)