View source for 8dep


==Cryo-EM structure of the human reduced folate carrier, apo condition==
<StructureSection load='8dep' size='340' side='right'caption='[[8dep]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dep]] 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=8DEP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DEP 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]] 3.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AJP:Digitonin'>AJP</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=8dep FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dep OCA], [https://pdbe.org/8dep PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dep RCSB], [https://www.ebi.ac.uk/pdbsum/8dep PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dep 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/C562_ECOLX C562_ECOLX] Electron-transport protein of unknown 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 ==
Folates are essential nutrients with important roles as cofactors in one-carbon transfer reactions, being heavily utilized in the synthesis of nucleic acids and the metabolism of amino acids during cell division(1,2). Mammals lack de novo folate synthesis pathways and thus rely on folate uptake from the extracellular milieu(3). The human reduced folate carrier (hRFC, also known as SLC19A1) is the major importer of folates into the cell(1,3), as well as chemotherapeutic agents such as methotrexate(4-6). As an anion exchanger, RFC couples the import of folates and antifolates to anion export across the cell membrane and it is a major determinant in methotrexate (antifolate) sensitivity, as genetic variants and its depletion result in drug resistance(4-8). Despite its importance, the molecular basis of substrate specificity by hRFC remains unclear. Here we present cryo-electron microscopy structures of hRFC in the apo state and captured in complex with methotrexate. Combined with molecular dynamics simulations and functional experiments, our study uncovers key determinants of hRFC transport selectivity among folates and antifolate drugs while shedding light on important features of anion recognition by hRFC.

Methotrexate recognition by the human reduced folate carrier SLC19A1.,Wright NJ, Fedor JG, Zhang H, Jeong P, Suo Y, Yoo J, Hong J, Im W, Lee SY Nature. 2022 Sep;609(7929):1056-1062. doi: 10.1038/s41586-022-05168-0. Epub 2022 , Sep 7. PMID:36071163<ref>PMID:36071163</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8dep" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fedor JG]]
[[Category: Lee S-Y]]
[[Category: Wright NJ]]