View source for 7bc7


==Cryo-EM structure of the proton coupled folate transporter at pH 6.0 bound to pemetrexed==
<StructureSection load='7bc7' size='340' side='right'caption='[[7bc7]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7bc7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BC7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BC7 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LYA:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC+ACID'>LYA</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=7bc7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bc7 OCA], [https://pdbe.org/7bc7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bc7 RCSB], [https://www.ebi.ac.uk/pdbsum/7bc7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bc7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PCFT_CHICK PCFT_CHICK] Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:34040256). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (PubMed:34040256). Functions at acidic pH via alternate outward- and inward-open conformation states (PubMed:34040256). Protonation of residues in the outward open state primes the protein for transport (PubMed:34040256). Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate (PubMed:34040256). Also able to transport antifolate drugs, such as methotrexate and pemetrexed (PubMed:34040256). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (By similarity). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (By similarity).[UniProtKB:Q96NT5]<ref>PMID:34040256</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine(1,2). Folate deficiency is associated with a number of developmental, immune and neurological disorders(3-5). Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body(3,6). The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus(4,7), and is an important route for the delivery of antifolate drugs in cancer chemotherapy(8-10). How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.

Structural basis of antifolate recognition and transport by PCFT.,Parker JL, Deme JC, Kuteyi G, Wu Z, Huo J, Goldman ID, Owens RJ, Biggin PC, Lea SM, Newstead S Nature. 2021 Jul;595(7865):130-134. doi: 10.1038/s41586-021-03579-z. Epub 2021 , May 26. PMID:34040256<ref>PMID:34040256</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7bc7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Gallus gallus]]
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Deme JC]]
[[Category: Lea SM]]
[[Category: Newstead S]]
[[Category: Parker JL]]