View source for 8jtv


==hOCT1 in complex with metformin in inward occluded conformation==
<StructureSection load='8jtv' size='340' side='right'caption='[[8jtv]], [[Resolution|resolution]] 3.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8jtv]] 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=8JTV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8JTV 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]] 3.77&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MF8:3-carbamimidoyl-1,1-dimethyl-guanidine'>MF8</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=8jtv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8jtv OCA], [https://pdbe.org/8jtv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8jtv RCSB], [https://www.ebi.ac.uk/pdbsum/8jtv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8jtv ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.

Structural insights into human organic cation transporter 1 transport and inhibition.,Zhang S, Zhu A, Kong F, Chen J, Lan B, He G, Gao K, Cheng L, Sun X, Yan C, Chen L, Liu X Cell Discov. 2024 Mar 15;10(1):30. doi: 10.1038/s41421-024-00664-1. PMID:38485705<ref>PMID:38485705</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8jtv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen J]]
[[Category: Chen L]]
[[Category: Cheng L]]
[[Category: Gao K]]
[[Category: He G]]
[[Category: Kong F]]
[[Category: Lan B]]
[[Category: Liu X]]
[[Category: Yan C]]
[[Category: Zhang S]]
[[Category: Zhu A]]