8sc2

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<table><tr><td colspan='2'>[[8sc2]] 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=8SC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SC2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8sc2]] 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=8SC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SC2 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]] 3.36&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.36&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C9F:Diltiazem'>C9F</scene></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C9F:[(2~{S},3~{S})-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxidanylidene-2,3-dihydro-1,5-benzothiazepin-3-yl]+ethanoate'>C9F</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=8sc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sc2 OCA], [https://pdbe.org/8sc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sc2 RCSB], [https://www.ebi.ac.uk/pdbsum/8sc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sc2 ProSAT]</span></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=8sc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sc2 OCA], [https://pdbe.org/8sc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sc2 RCSB], [https://www.ebi.ac.uk/pdbsum/8sc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sc2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[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:9260930, PubMed:9187257, PubMed:11388889, PubMed:9655880, PubMed:11408531, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:12439218, PubMed:12719534). 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:9260930, PubMed:24961373, PubMed:35469921, PubMed:12439218). 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:9260930, PubMed:11408531, PubMed:15389554, PubMed:35469921).[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>
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[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>
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== Publication Abstract from PubMed ==
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Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.
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Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.,Zeng YC, Sobti M, Quinn A, Smith NJ, Brown SHJ, Vandenberg JI, Ryan RM, O'Mara ML, Stewart AG Nat Commun. 2023 Oct 11;14(1):6374. doi: 10.1038/s41467-023-42086-9. PMID:37821493<ref>PMID:37821493</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 8sc2" style="background-color:#fffaf0;"></div>
== References ==
== References ==
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<references/>

Current revision

Human OCT1 bound to diltiazem in inward-open conformation

PDB ID 8sc2

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