7q3b

From Proteopedia

(Difference between revisions)

Revision as of 05:49, 31 May 2023

Crystal structure of human STING in complex with 3'3'-c-(2'F,2'dA-isonucA)MP

Structural highlights

7q3b 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.
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) is an adaptor protein of the cGAS-STING signaling pathway involved in the sensing of cytosolic DNA. It functions as a receptor for cyclic dinucleotides (CDNs) and, upon their binding, mediates cytokine expression and host immunity. Besides naturally occurring CDNs, various synthetic CDNs, such as ADU-S100, have been reported to effectively activate STING and are being evaluated in clinical trials for the treatment of cancer. Here, we describe the preparation of a unique new class of STING agonists: isonucleotidic cyclic dinucleotides and the synthesis of their prodrugs. The presented CDNs stimulate STING with comparable efficiency to ADU-S100, whereas their prodrugs demonstrate activity up to four orders of magnitude better due to the improved cellular uptake. The compounds are very potent inducers of inflammatory cytokines by peripheral blood mononuclear cells (PBMCs). We also report the X-ray crystal structure of the lead inhibitor bound to the wild-type (WT) STING.

Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential.,Dejmek M, Sala M, Brazdova A, Vanekova L, Smola M, Klima M, Brehova P, Budesinsky M, Dracinsky M, Prochazkova E, Zavrel M, Simak O, Pav O, Boura E, Birkus G, Nencka R Structure. 2022 Jun 2. pii: S0969-2126(22)00186-1. doi:, 10.1016/j.str.2022.05.012. PMID:35690061^[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
↑ Dejmek M, Sala M, Brazdova A, Vanekova L, Smola M, Klima M, Brehova P, Budesinsky M, Dracinsky M, Prochazkova E, Zavrel M, Simak O, Pav O, Boura E, Birkus G, Nencka R. Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential. Structure. 2022 Jun 2. pii: S0969-2126(22)00186-1. doi:, 10.1016/j.str.2022.05.012. PMID:35690061 doi:http://dx.doi.org/10.1016/j.str.2022.05.012

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7q3b"

Categories: Homo sapiens | Large Structures | Boura E | Klima M | Smola M

@@ Line 3: / Line 3: @@
 <StructureSection load='7q3b' size='340' side='right'caption='[[7q3b]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7q3b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q3B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7q3b]] 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=7Q3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q3B FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8SC:33-c-(2F,2dA-isonucA)MP'>8SC</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=7q3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q3b OCA], [https://pdbe.org/7q3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q3b RCSB], [https://www.ebi.ac.uk/pdbsum/7q3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q3b 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 ==
@@ Line 20: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Boura, E]]
+[[Category: Boura E]]
-[[Category: Klima, M]]
+[[Category: Klima M]]
-[[Category: Smola, M]]
+[[Category: Smola M]]
-[[Category: Activator]]
-[[Category: Antiviral]]
-[[Category: Immune system]]
-[[Category: Sting]]

7q3b

From Proteopedia

Revision as of 05:49, 31 May 2023

Crystal structure of human STING in complex with 3'3'-c-(2'F,2'dA-isonucA)MP

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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