8gt6
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==human STING With agonist HB3089== | |
| + | <StructureSection load='8gt6' size='340' side='right'caption='[[8gt6]], [[Resolution|resolution]] 3.47Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8gt6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8GT6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GT6 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WJ6:1-[(2E)-4-{5-carbamoyl-2-[(1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)amino]-7-[3-(morpholin-4-yl)propoxy]-1H-benzimidazol-1-yl}but-2-en-1-yl]-2-[(1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxamide'>WJ6</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=8gt6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gt6 OCA], [https://pdbe.org/8gt6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gt6 RCSB], [https://www.ebi.ac.uk/pdbsum/8gt6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gt6 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/STING_HUMAN STING_HUMAN] Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway.<ref>PMID:18818105</ref> <ref>PMID:18724357</ref> <ref>PMID:19776740</ref> <ref>PMID:19433799</ref> <ref>PMID:21074459</ref> <ref>PMID:21947006</ref> <ref>PMID:23258412</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. Herein, we designed a novel STING agonist, designated as HB3089 that exhibits robust and durable anti-tumor activity in tumor models across various cancer types. Cryo-EM analysis reveals that HB3089-bound human STING has structural changes similar to that of the STING mutant V147L, a constitutively activated mutant identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). Both structures highlight the conformational changes of the transmembrane domain (TMD), but without the 180 degrees -rotation of the ligand binding domain (LBD) previously shown to be required for STING activation. Further structure-based functional analysis confirmed a new STING activation mode shared by the agonist and the SAVI-related mutation, in which the connector linking the LBD and the TMD senses the activation signal and controls the conformational changes of the LBD and the TMD for STING activation. Together, our findings lead to a new working model for STING activation and open a new avenue for the rationale design of STING-targeted therapies either for cancer or autoimmune disorders. | ||
| - | + | Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation.,Xie Z, Wang Z, Fan F, Zhou J, Hu Z, Wang Q, Wang X, Zeng Q, Zhang Y, Qiu J, Zhou X, Xu H, Bai H, Zhan Z, Ding J, Zhang H, Duan W, Yu X, Geng M Cell Discov. 2022 Dec 13;8(1):133. doi: 10.1038/s41421-022-00481-4. PMID:36513640<ref>PMID:36513640</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8gt6" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Wang Z]] | ||
| + | [[Category: Yu X]] | ||
Revision as of 09:12, 28 December 2022
human STING With agonist HB3089
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