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==Structural Basis for Inhibitor-Induced Aggregation of HIV-1 Integrase== | |||
<StructureSection load='5hot' size='340' side='right'caption='[[5hot]], [[Resolution|resolution]] 4.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5hot]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HOT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HOT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 4.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2SQ:(2S)-TERT-BUTOXY[4-(8-FLUORO-5-METHYL-3,4-DIHYDRO-2H-CHROMEN-6-YL)-2-METHYL-1-OXO-1,2-DIHYDROISOQUINOLIN-3-YL]ETHANOIC+ACID'>2SQ</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5hot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hot OCA], [https://pdbe.org/5hot PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hot RCSB], [https://www.ebi.ac.uk/pdbsum/5hot PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hot ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q72498_9HIV1 Q72498_9HIV1] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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 A 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. | |||
Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.,Gupta K, Turkki V, Sherrill-Mix S, Hwang Y, Eilers G, Taylor L, McDanal C, Wang P, Temelkoff D, Nolte RT, Velthuisen E, Jeffrey J, Van Duyne GD, Bushman FD PLoS Biol. 2016 Dec 9;14(12):e1002584. doi: 10.1371/journal.pbio.1002584., eCollection 2016 Dec. PMID:27935939<ref>PMID:27935939</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5hot" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Retroviral integrase 3D structures|Retroviral integrase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Temelkoff | [[Category: Large Structures]] | ||
[[Category: | [[Category: Bushman FD]] | ||
[[Category: | [[Category: Eilers G]] | ||
[[Category: | [[Category: Gupta K]] | ||
[[Category: | [[Category: Hwang Y]] | ||
[[Category: Jeffrey J]] | |||
[[Category: McDanal C]] | |||
[[Category: Nolte R]] | |||
[[Category: Sherrill-Mix S]] | |||
[[Category: Taylor L]] | |||
[[Category: Temelkoff D]] | |||
[[Category: Turkki V]] | |||
[[Category: Van Duyne GD]] | |||
[[Category: Velthuisen E]] | |||
[[Category: Wang P]] | |||
Latest revision as of 13:49, 16 August 2023
Structural Basis for Inhibitor-Induced Aggregation of HIV-1 IntegraseStructural Basis for Inhibitor-Induced Aggregation of HIV-1 Integrase
Structural highlights
FunctionPublication Abstract from PubMedThe 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 A 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. Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.,Gupta K, Turkki V, Sherrill-Mix S, Hwang Y, Eilers G, Taylor L, McDanal C, Wang P, Temelkoff D, Nolte RT, Velthuisen E, Jeffrey J, Van Duyne GD, Bushman FD PLoS Biol. 2016 Dec 9;14(12):e1002584. doi: 10.1371/journal.pbio.1002584., eCollection 2016 Dec. PMID:27935939[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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