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| <StructureSection load='7ke0' size='340' side='right'caption='[[7ke0]], [[Resolution|resolution]] 2.19Å' scene=''> | | <StructureSection load='7ke0' size='340' side='right'caption='[[7ke0]], [[Resolution|resolution]] 2.19Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7ke0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KE0 FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KE0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KE0 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WBV:(2S)-tert-butoxy{4-(4-chlorophenyl)-2,3,6-trimethyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetic+acid'>WBV</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.19Å</td></tr> |
| <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene></td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene>, <scene name='pdbligand=WBV:(2S)-tert-butoxy{4-(4-chlorophenyl)-2,3,6-trimethyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetic+acid'>WBV</scene></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] </span></td></tr>
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| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ke0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ke0 OCA], [https://pdbe.org/7ke0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ke0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ke0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ke0 ProSAT]</span></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=7ke0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ke0 OCA], [https://pdbe.org/7ke0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ke0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ke0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ke0 ProSAT]</span></td></tr> |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial.
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| A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.,Maehigashi T, Ahn S, Kim UI, Lindenberger J, Oo A, Koneru PC, Mahboubi B, Engelman AN, Kvaratskhelia M, Kim K, Kim B PLoS Pathog. 2021 Jul 22;17(7):e1009671. doi: 10.1371/journal.ppat.1009671., eCollection 2021 Jul. PMID:34293041<ref>PMID:34293041</ref>
| | ==See Also== |
| | | *[[Retroviral integrase 3D structures|Retroviral integrase 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7ke0" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: RNA-directed DNA polymerase]]
| | [[Category: Kvaratskhelia M]] |
| [[Category: Kvaratskhelia, M]] | | [[Category: Lindenberger JJ]] |
| [[Category: Lindenberger, J J]] | |
| [[Category: Hiv]]
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| [[Category: Inhibitor]]
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| [[Category: Integrase]]
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| [[Category: Transferase-inhibitor complex]]
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