title: Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kushol
authors.identifier: http://orcid.org/0000-0002-7006-2667
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Vesa
authors.identifier: http://orcid.org/0000-0001-9626-1966
authors.initials: V
authors.lastname: Turkki
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Sherrill-Mix
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Young
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Grant
authors.initials: G
authors.lastname: Eilers
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Louis
authors.identifier: http://orcid.org/0000-0002-6993-5838
authors.initials: L
authors.lastname: Taylor
authors.affiliation: HIV DPU, Infectious Disease Therapy Area Unit GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Charlene
authors.initials: C
authors.lastname: McDanal
authors.affiliation: HIV DPU, Infectious Disease Therapy Area Unit GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: HIV DPU, Infectious Disease Therapy Area Unit GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Temelkoff
authors.affiliation: Protein Cellular and Structural Science, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America.
authors.forename: Robert T
authors.identifier: http://orcid.org/0000-0003-1876-2049
authors.initials: RT
authors.lastname: Nolte
authors.affiliation: HIV DPU, Infectious Disease Therapy Area Unit GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Emile
authors.identifier: http://orcid.org/0000-0001-5781-8805
authors.initials: E
authors.lastname: Velthuisen
authors.affiliation: HIV DPU, Infectious Disease Therapy Area Unit GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Jerry
authors.identifier: http://orcid.org/0000-0001-7303-8737
authors.initials: J
authors.lastname: Jeffrey
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gregory D
authors.identifier: http://orcid.org/0000-0003-0247-1626
authors.initials: GD
authors.lastname: Van Duyne
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Frederic D
authors.identifier: http://orcid.org/0000-0003-4740-4056
authors.initials: FD
authors.lastname: Bushman
mesh_terms: D000494:Allosteric Regulation; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D015394:Molecular Structure
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase