8et6
From Proteopedia
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(New page: '''Unreleased structure''' The entry 8et6 is ON HOLD Authors: Description: Category: Unreleased Structures) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Cryo-EM structure of the organic cation transporter 1 in the apo state== | |
| + | <StructureSection load='8et6' size='340' side='right'caption='[[8et6]], [[Resolution|resolution]] 3.57Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8et6]] 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=8ET6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ET6 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]] 3.57Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=8et6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8et6 OCA], [https://pdbe.org/8et6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8et6 RCSB], [https://www.ebi.ac.uk/pdbsum/8et6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8et6 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/S22A1_HUMAN S22A1_HUMAN] Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930).[UniProtKB:O08966][UniProtKB:Q63089]<ref>PMID:11388889</ref> <ref>PMID:11408531</ref> <ref>PMID:11907186</ref> <ref>PMID:12439218</ref> <ref>PMID:12719534</ref> <ref>PMID:15389554</ref> <ref>PMID:15817714</ref> <ref>PMID:16263091</ref> <ref>PMID:16272756</ref> <ref>PMID:16581093</ref> <ref>PMID:17460754</ref> <ref>PMID:19536068</ref> <ref>PMID:21128598</ref> <ref>PMID:23680637</ref> <ref>PMID:24961373</ref> <ref>PMID:34040533</ref> <ref>PMID:35469921</ref> <ref>PMID:9187257</ref> <ref>PMID:9260930</ref> <ref>PMID:9655880</ref> <ref>PMID:35307651</ref> Mediates the uptake of 1-methyl-4-phenylpyridinium (MPP(+)).<ref>PMID:11388889</ref> Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).<ref>PMID:11388889</ref> Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).<ref>PMID:11388889</ref> Not able to uptake 1-methyl-4-phenylpyridinium (MPP(+)).<ref>PMID:11388889</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A wide range of endogenous and xenobiotic organic ions require facilitated transport systems to cross the plasma membrane for their disposition. In mammals, organic cation transporter (OCT) subtypes 1 and 2 (OCT1 and OCT2, also known as SLC22A1 and SLC22A2, respectively) are polyspecific transporters responsible for the uptake and clearance of structurally diverse cationic compounds in the liver and kidneys, respectively. Notably, it is well established that human OCT1 and OCT2 play central roles in the pharmacokinetics and drug-drug interactions of many prescription medications, including metformin. Despite their importance, the basis of polyspecific cationic drug recognition and the alternating access mechanism for OCTs have remained a mystery. Here we present four cryo-electron microscopy structures of apo, substrate-bound and drug-bound OCT1 and OCT2 consensus variants, in outward-facing and outward-occluded states. Together with functional experiments, in silico docking and molecular dynamics simulations, these structures uncover general principles of organic cation recognition by OCTs and provide insights into extracellular gate occlusion. Our findings set the stage for a comprehensive structure-based understanding of OCT-mediated drug-drug interactions, which will prove critical in the preclinical evaluation of emerging therapeutics. | ||
| - | + | Molecular basis of polyspecific drug and xenobiotic recognition by OCT1 and OCT2.,Suo Y, Wright NJ, Guterres H, Fedor JG, Butay KJ, Borgnia MJ, Im W, Lee SY Nat Struct Mol Biol. 2023 Jul;30(7):1001-1011. doi: 10.1038/s41594-023-01017-4. , Epub 2023 Jun 8. PMID:37291422<ref>PMID:37291422</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8et6" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lee S-Y]] | ||
| + | [[Category: Suo Y]] | ||
| + | [[Category: Wright NJ]] | ||
Current revision
Cryo-EM structure of the organic cation transporter 1 in the apo state
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