View source for 7xq0


==Structure of hSLC19A1+3'3'-CDA==
<StructureSection load='7xq0' size='340' side='right'caption='[[7xq0]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xq0]] 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=7XQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XQ0 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2BA:(2R,3R,3AS,5R,7AR,9R,10R,10AS,12R,14AR)-2,9-BIS(6-AMINO-9H-PURIN-9-YL)OCTAHYDRO-2H,7H-DIFURO[3,2-D 3,2-J][1,3,7,9,2,8]TETRAOXADIPHOSPHACYCLODODECINE-3,5,10,12-TETROL+5,12-DIOXIDE'>2BA</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=7xq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xq0 OCA], [https://pdbe.org/7xq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xq0 RCSB], [https://www.ebi.ac.uk/pdbsum/7xq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xq0 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/S19A1_HUMAN S19A1_HUMAN] The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/S19A1_HUMAN S19A1_HUMAN] Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31126740, PubMed:31511694, PubMed:32276275, PubMed:7826387, PubMed:9041240). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31126740, PubMed:31511694). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:22554803, PubMed:7615551, PubMed:7641195, PubMed:9767079). Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses (PubMed:31126740, PubMed:31511694, PubMed:36745868). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803).<ref>PMID:10787414</ref> <ref>PMID:14609557</ref> <ref>PMID:15337749</ref> <ref>PMID:16115875</ref> <ref>PMID:22554803</ref> <ref>PMID:31126740</ref> <ref>PMID:31511694</ref> <ref>PMID:32276275</ref> <ref>PMID:36745868</ref> <ref>PMID:7615551</ref> <ref>PMID:7641195</ref> <ref>PMID:7826387</ref> <ref>PMID:9041240</ref> <ref>PMID:9767079</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life(1,2). Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals(3-7). 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses(8-21). Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A1(22,23). Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics(24,25), thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.

Recognition of cyclic dinucleotides and folates by human SLC19A1.,Zhang Q, Zhang X, Zhu Y, Sun P, Zhang L, Ma J, Zhang Y, Zeng L, Nie X, Gao Y, Li Z, Liu S, Lou J, Gao A, Zhang L, Gao P Nature. 2022 Dec;612(7938):170-176. doi: 10.1038/s41586-022-05452-z. Epub 2022 , Oct 20. PMID:36265513<ref>PMID:36265513</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7xq0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gao A]]
[[Category: Gao P]]
[[Category: Sun PP]]
[[Category: Zhang LG]]
[[Category: Zhang QX]]
[[Category: Zhang XY]]
[[Category: Zhu YL]]