7kvx

From Proteopedia

(Difference between revisions)

Current revision

Structure of hSTING in complex with novel carbocyclic pyrimidine CDN 1

Structural highlights

7kvx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.48Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.,Vyskocil S, Cardin D, Ciavarri J, Conlon J, Cullis C, England D, Gershman R, Gigstad K, Gipson K, Gould A, Greenspan P, Griffin R, Gulavita N, Harrison S, Hu Z, Hu Y, Hata A, Huang J, Huang SC, Janowick D, Jones M, Kolev V, Langston SP, Lee HM, Li G, Lok D, Ma L, Mai D, Malley J, Matsuda A, Mizutani H, Mizutani M, Molchanova N, Nunes E, Pusalkar S, Renou C, Rowland S, Sato Y, Shaw M, Shen L, Shi Z, Skene R, Soucy F, Stroud S, Xu H, Xu T, Abu-Yousif AO, Zhang J J Med Chem. 2021 May 27;64(10):6902-6923. doi: 10.1021/acs.jmedchem.1c00374. Epub, 2021 May 17. PMID:34000802^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Vyskocil S, Cardin D, Ciavarri J, Conlon J, Cullis C, England D, Gershman R, Gigstad K, Gipson K, Gould A, Greenspan P, Griffin R, Gulavita N, Harrison S, Hu Z, Hu Y, Hata A, Huang J, Huang SC, Janowick D, Jones M, Kolev V, Langston SP, Lee HM, Li G, Lok D, Ma L, Mai D, Malley J, Matsuda A, Mizutani H, Mizutani M, Molchanova N, Nunes E, Pusalkar S, Renou C, Rowland S, Sato Y, Shaw M, Shen L, Shi Z, Skene R, Soucy F, Stroud S, Xu H, Xu T, Abu-Yousif AO, Zhang J. Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route. J Med Chem. 2021 May 27;64(10):6902-6923. doi: 10.1021/acs.jmedchem.1c00374. Epub, 2021 May 17. PMID:34000802 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00374

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7kvx"

Categories: Homo sapiens | Large Structures | Skene R

@@ Line 1: / Line 1: @@
 ==Structure of hSTING in complex with novel carbocyclic pyrimidine CDN 1==
-<StructureSection load='7kvx' size='340' side='right'caption='[[7kvx]]' scene=''>
+<StructureSection load='7kvx' size='340' side='right'caption='[[7kvx]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KVX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KVX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7kvx]] 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=7KVX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KVX FirstGlance]. <br>
-</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=7kvx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kvx OCA], [https://pdbe.org/7kvx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kvx RCSB], [https://www.ebi.ac.uk/pdbsum/7kvx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kvx ProSAT]</span></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]] 2.48&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=X5J:(2R,5R,7R,8R,10R,12aR,14R,15aS,16R)-7-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-16-hydroxy-14-[(pyrimidin-4-yl)amino]-2,10-disulfanyldecahydro-2H,10H-5,8-methano-2lambda~5~,10lambda~5~-cyclopenta[l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecine-2,10-dione'>X5J</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=7kvx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kvx OCA], [https://pdbe.org/7kvx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kvx RCSB], [https://www.ebi.ac.uk/pdbsum/7kvx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kvx 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 Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
+Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.,Vyskocil S, Cardin D, Ciavarri J, Conlon J, Cullis C, England D, Gershman R, Gigstad K, Gipson K, Gould A, Greenspan P, Griffin R, Gulavita N, Harrison S, Hu Z, Hu Y, Hata A, Huang J, Huang SC, Janowick D, Jones M, Kolev V, Langston SP, Lee HM, Li G, Lok D, Ma L, Mai D, Malley J, Matsuda A, Mizutani H, Mizutani M, Molchanova N, Nunes E, Pusalkar S, Renou C, Rowland S, Sato Y, Shaw M, Shen L, Shi Z, Skene R, Soucy F, Stroud S, Xu H, Xu T, Abu-Yousif AO, Zhang J J Med Chem. 2021 May 27;64(10):6902-6923. doi: 10.1021/acs.jmedchem.1c00374. Epub, 2021 May 17. PMID:34000802<ref>PMID:34000802</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7kvx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Stimulator of interferon genes protein 3D structures|Stimulator of interferon genes protein 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Skene R]]

7kvx

From Proteopedia

Current revision

Structure of hSTING in complex with novel carbocyclic pyrimidine CDN 1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox