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| | ==Crystal structure of human STING (G230A, H232R, R293Q) in complex with Compound 18== | | ==Crystal structure of human STING (G230A, H232R, R293Q) in complex with Compound 18== |
| - | <StructureSection load='6mxe' size='340' side='right' caption='[[6mxe]], [[Resolution|resolution]] 2.47Å' scene=''> | + | <StructureSection load='6mxe' size='340' side='right'caption='[[6mxe]], [[Resolution|resolution]] 2.47Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6mxe]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MXE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MXE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6mxe]] 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=6MXE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MXE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K5S:[(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]acetic+acid'>K5S</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]] 2.47Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TMEM173, ERIS, MITA, STING ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=K5S:[(3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]acetic+acid'>K5S</scene></td></tr> |
| - | <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=6mxe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mxe OCA], [http://pdbe.org/6mxe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mxe RCSB], [http://www.ebi.ac.uk/pdbsum/6mxe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mxe 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=6mxe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mxe OCA], [https://pdbe.org/6mxe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mxe RCSB], [https://www.ebi.ac.uk/pdbsum/6mxe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mxe ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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 ==
| + | |
| - | Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein-ligand as well as ligand-ligand interactions. Successful implementation of this strategy led to the identification of 18, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.
| + | |
| | | | |
| - | Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING.,Siu T, Altman MD, Baltus GA, Childers M, Ellis JM, Gunaydin H, Hatch H, Ho T, Jewell J, Lacey BM, Lesburg CA, Pan BS, Sauvagnat B, Schroeder GK, Xu S ACS Med Chem Lett. 2018 Dec 6;10(1):92-97. doi: 10.1021/acsmedchemlett.8b00466., eCollection 2019 Jan 10. PMID:30655953<ref>PMID:30655953</ref>
| + | ==See Also== |
| - | | + | *[[Stimulator of interferon genes protein|Stimulator of interferon genes protein]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6mxe" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ho, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Lesburg, C A]] | + | [[Category: Ho T]] |
| - | [[Category: Siu, T]]
| + | [[Category: Lesburg CA]] |
| - | [[Category: Immune system]] | + | [[Category: Siu T]] |
| - | [[Category: Immune system-inhibitor complex]] | + | |
| - | [[Category: Innate immunity]]
| + | |
| - | [[Category: Open conformation]]
| + | |
| - | [[Category: Signaling]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4] [5] [6] [7]
See Also
References
- ↑ Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu HB. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008 Oct 17;29(4):538-50. doi: 10.1016/j.immuni.2008.09.003. Epub 2008 , Sep 25. PMID:18818105 doi:10.1016/j.immuni.2008.09.003
- ↑ Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008 Oct 2;455(7213):674-8. doi: 10.1038/nature07317. Epub 2008 Aug 24. PMID:18724357 doi:10.1038/nature07317
- ↑ Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009 Oct 8;461(7265):788-92. doi: 10.1038/nature08476. Epub 2009 Sep 23. PMID:19776740 doi:10.1038/nature08476
- ↑ Sun W, Li Y, Chen L, Chen H, You F, Zhou X, Zhou Y, Zhai Z, Chen D, Jiang Z. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009 May 26;106(21):8653-8. doi:, 10.1073/pnas.0900850106. Epub 2009 May 11. PMID:19433799 doi:10.1073/pnas.0900850106
- ↑ Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity. 2010 Nov 24;33(5):765-76. doi: 10.1016/j.immuni.2010.10.013. Epub 2010 , Nov 11. PMID:21074459 doi:10.1016/j.immuni.2010.10.013
- ↑ Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011 Sep 25;478(7370):515-8. doi: 10.1038/nature10429. PMID:21947006 doi:10.1038/nature10429
- ↑ Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science. 2013 Feb 15;339(6121):826-30. doi: 10.1126/science.1229963. Epub 2012, Dec 20. PMID:23258412 doi:10.1126/science.1229963
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