9qvt
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of STING CTD in complex with potent agonist D5== | |
| + | <StructureSection load='9qvt' size='340' side='right'caption='[[9qvt]], [[Resolution|resolution]] 2.31Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9qvt]] is a 1 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=9QVT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9QVT 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]] 2.305Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JA0:4-[6-methoxy-5-[[6-methoxy-2-(4-oxidanyl-4-oxidanylidene-butanoyl)-1-benzothiophen-5-yl]sulfanylmethylsulfanyl]-1-benzothiophen-2-yl]-4-oxidanylidene-butanoic+acid'>A1JA0</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=9qvt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9qvt OCA], [https://pdbe.org/9qvt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9qvt RCSB], [https://www.ebi.ac.uk/pdbsum/9qvt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9qvt 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 == | ||
| + | Pharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumour-specific or conditionally activated STING agonists for enhanced safety and efficacy. Here we explore an unconventional prodrug activation strategy for on-tumour synthesis of a potent agonist. Leveraging the unique mechanism of MSA2, a small-molecule agonist that dimerizes non-covalently before binding to STING, we showed that its analogues bearing reactive functional groups readily and selectively form covalent dimers under mild conditions and in complex environments. We identified a reacting pair that led to a thioether-linked dimer with submicromolar potency in cell-based assays. Caging one of the reactants with a self-immolative beta-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumours overexpressing beta-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors. | ||
| - | + | Tumour-specific STING agonist synthesis via a two-component prodrug system.,Hsu NS, Tang C, Mendes RV, Labao-Almeida C, Dos Reis CV, Coelho AR, Marques MC, Cabeza Cabrerizo M, Misteli R, Rooney TPC, Hyvonen M, Corzana F, Fior R, Bernardes GJL Nat Chem. 2025 Sep 16. doi: 10.1038/s41557-025-01930-9. PMID:40957952<ref>PMID:40957952</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9qvt" style="background-color:#fffaf0;"></div> |
| - | [[Category: Bernardes | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: Hyvonen | + | __TOC__ |
| - | [[Category: Rooney | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| + | [[Category: Large Structures]] | ||
| + | [[Category: Bernardes GJL]] | ||
| + | [[Category: Hsu N-S]] | ||
| + | [[Category: Hyvonen M]] | ||
| + | [[Category: Rooney T]] | ||
| + | [[Category: Skidmore J]] | ||
| + | [[Category: Dos Reis CV]] | ||
Current revision
Crystal structure of STING CTD in complex with potent agonist D5
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