View source for 6ukm


==STING C-terminal Domain Complexed with Non-cyclic Dinucleotide Compound MSA-2==
<StructureSection load='6ukm' size='340' side='right'caption='[[6ukm]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ukm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UKM 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]] 1.74&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QAD:4-(5,6-dimethoxy-1-benzothiophen-2-yl)-4-oxobutanoic+acid'>QAD</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=6ukm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ukm OCA], [https://pdbe.org/6ukm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ukm RCSB], [https://www.ebi.ac.uk/pdbsum/6ukm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ukm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SMT3_YEAST SMT3_YEAST] Not known; suppressor of MIF2 mutations.[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 the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-beta secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

An orally available non-nucleotide STING agonist with antitumor activity.,Pan BS, Perera SA, Piesvaux JA, Presland JP, Schroeder GK, Cumming JN, Trotter BW, Altman MD, Buevich AV, Cash B, Cemerski S, Chang W, Chen Y, Dandliker PJ, Feng G, Haidle A, Henderson T, Jewell J, Kariv I, Knemeyer I, Kopinja J, Lacey BM, Laskey J, Lesburg CA, Liang R, Long BJ, Lu M, Ma Y, Minnihan EC, O'Donnell G, Otte R, Price L, Rakhilina L, Sauvagnat B, Sharma S, Tyagarajan S, Woo H, Wyss DF, Xu S, Bennett DJ, Addona GH Science. 2020 Aug 21;369(6506). pii: 369/6506/eaba6098. doi:, 10.1126/science.aba6098. PMID:32820094<ref>PMID:32820094</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ukm" style="background-color:#fffaf0;"></div>

==See Also==
*[[Stimulator of interferon genes protein|Stimulator of interferon genes protein]]
*[[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: Saccharomyces cerevisiae S288C]]
[[Category: Lesburg CA]]