Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural insights into human organic cation transporter 1 transport and inhibition.
Journal, issue, pages	Cell Discov, Vol. 10, Issue 1, Page 30, Year 2024
Publish date	Mar 15, 2024
Authors	Shuhao Zhang / Angqi Zhu / Fang Kong / Jianan Chen / Baoliang Lan / Guodong He / Kaixuan Gao / Lili Cheng / Xiaoou Sun / Chuangye Yan / Ligong Chen / Xiangyu Liu /
PubMed Abstract	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 ...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.
External links	Cell Discov / PubMed:38485705 / PubMed Central
Methods	EM (single particle)
Resolution	2.98 - 4.14 Å
Structure data	36651 8jts EMDB-36651, PDB-8jts: hOCT1 in complex with metformin in outward open conformation Method: EM (single particle) / Resolution: 4.14 Å 36652 8jtt EMDB-36652, PDB-8jtt: hOCT1 in complex with metformin in outward occluded conformation Method: EM (single particle) / Resolution: 3.87 Å 36653 8jtv EMDB-36653, PDB-8jtv: hOCT1 in complex with metformin in inward occluded conformation Method: EM (single particle) / Resolution: 3.77 Å 36654 8jtw EMDB-36654, PDB-8jtw: hOCT1 in complex with nb5660 in inward facing partially open 1 conformation Method: EM (single particle) / Resolution: 3.23 Å 36655 8jtx EMDB-36655, PDB-8jtx: hOCT1 in complex with nb5660 in inward facing fully open conformation Method: EM (single particle) / Resolution: 3.28 Å 36656 8jty EMDB-36656, PDB-8jty: hOCT1 in complex with nb5660 in inward facing partially open 2 conformation Method: EM (single particle) / Resolution: 3.26 Å 36657 8jtz EMDB-36657, PDB-8jtz: hOCT1 in complex with spironolactone in outward facing partially occluded conformation Method: EM (single particle) / Resolution: 3.27 Å 36658 8ju0 EMDB-36658, PDB-8ju0: hOCT1 in complex with spironolactone in inward facing occluded conformation Method: EM (single particle) / Resolution: 2.98 Å
Chemicals	ChemComp-MF8: Metformin / medication, antipsychoticYM ChemComp-SNL: SPIRONOLACTONE / medicationYM
Source	homo sapiens (human) lama glama (llama)
Keywords	MEMBRANE PROTEIN / SLC / transporter