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6rst

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'''Unreleased structure'''
 
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The entry 6rst is ON HOLD until Paper Publication
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==TBK1 in complex with inhibitor compound 24==
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<StructureSection load='6rst' size='340' side='right'caption='[[6rst]], [[Resolution|resolution]] 3.29&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6rst]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RST OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RST FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KHQ:1-[4-[(1~{R})-1-[2-[[5-[1-(cyclopropylmethyl)pyrazol-4-yl]-1~{H}-benzimidazol-2-yl]amino]pyridin-4-yl]ethyl]piperazin-1-yl]-3,3,3-tris(fluoranyl)propan-1-one'>KHQ</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6rst FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rst OCA], [http://pdbe.org/6rst PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rst RCSB], [http://www.ebi.ac.uk/pdbsum/6rst PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rst ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/TBK1_HUMAN TBK1_HUMAN]] Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFN-alpha and IFN-beta. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS or SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1. Phosphorylates Borna disease virus (BDV) P protein.<ref>PMID:10581243</ref> <ref>PMID:10783893</ref> <ref>PMID:11839743</ref> <ref>PMID:12692549</ref> <ref>PMID:12702806</ref> <ref>PMID:14703513</ref> <ref>PMID:15485837</ref> <ref>PMID:15489227</ref> <ref>PMID:15367631</ref> <ref>PMID:18583960</ref> <ref>PMID:21270402</ref> <ref>PMID:21464307</ref> <ref>PMID:21617041</ref> <ref>PMID:21138416</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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. The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKepsilon are non-canonical members of the inhibitor of nuclear factor kappaB (IkappaB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKepsilon inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 (IRF3) and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2, but showed only weak to moderate antitumor activity in the SK-MEL-2 human melanoma xenograft model.
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Authors:
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Discovery of BAY-985 a highly selective TBK1/Ikkepsilon inhibitor.,Lefranc J, Schulze VK, Hillig RC, Briem H, Prinz F, Mengel A, Heinrich T, Balint J, Rengachari S, Irlbacher H, Stockigt D, Bomer U, Bader B, Gradl SN, Nising CF, von Nussbaum F, Mumberg D, Panne D, Wengner A J Med Chem. 2019 Dec 20. doi: 10.1021/acs.jmedchem.9b01460. PMID:31859507<ref>PMID:31859507</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6rst" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Hillig, R C]]
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[[Category: Panne, D]]
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[[Category: Rengachari, S]]
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[[Category: Immune system]]
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[[Category: Innate immunity]]
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[[Category: Kinase]]
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[[Category: Small molecule inhibitor]]

Revision as of 08:21, 1 January 2020

TBK1 in complex with inhibitor compound 24

PDB ID 6rst

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