Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase

Gupta, Kushol; Turkki, Vesa; Sherrill-Mix, Scott; Hwang, Young; Eilers, Grant; Taylor, Louis; McDanal, Charlene; Wang, Ping; Temelkoff, David; Nolte, Robert T.; Velthuisen, Emile; Jeffrey, Jerry; Van Duyne, Gregory D.; Bushman, Frederic D.; Rowland-Jones, Sarah L.

doi:10.1371/journal.pbio.1002584

Title: Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase

Journal Article · Fri Dec 09 00:00:00 EST 2016 · PLoS Biology (Online)

DOI:https://doi.org/10.1371/journal.pbio.1002584· OSTI ID:1419080

^[1];

^[1]; Sherrill-Mix, Scott ^[1]; Hwang, Young ^[1]; Eilers, Grant ^[1];

^[1]; McDanal, Charlene ^[2]; Wang, Ping ^[2]; Temelkoff, David ^[2];

^[3];

^[2];

^[1];

^[1]; Rowland-Jones, Sarah L. ^[4]

Univ. of Pennsylvania, Philadelphia, PA (United States)
GlaxoSmithKline, Research Triangle Park, NC (United States)
GlaxoSmithKline, Collegeville, PA (United States)
Weatherall Institute of Molecular Medicine, Oxford (England)

The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); NIGMS

Grant/Contract Number:: AC02-05CH11231; R01 AI 052845; P30 AI 045008

OSTI ID:: 1419080

Journal Information:: PLoS Biology (Online), Vol. 14, Issue 12; ISSN 1545-7885

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
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crystal structure
HIV-1
viral replication
dimers (Chemical physics)
polymers
substitution mutation
virions

Title: Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase

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