Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase

• Published in: PLoS biology 2016-12, Vol.14 (12), p.e1002584-e1002584
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Allosteric Regulation; BASIC BIOLOGICAL SCIENCES; Biology and Life Sciences; Biophysics; Colleges & universities; crystal structure; dimers (Chemical physics); Experiments; Genetic aspects; HIV; HIV infection; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1; HIV-1 - enzymology; Infectious diseases; Laboratories; Lentivirus; Medical research; Medicine; Medicine and Health Sciences; Methods; Microscopy; Molecular Structure; Mutation; Physical Sciences; polymers; Proteins; Retroviridae; RNA sequencing; Sedimentation & deposition; substitution mutation; viral replication; virions
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002584

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.