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Structure paper

TitleStructural insights into human organic cation transporter 1 transport and inhibition.
Journal, issue, pagesCell Discov, Vol. 10, Issue 1, Page 30, Year 2024
Publish dateMar 15, 2024
AuthorsShuhao Zhang / Angqi Zhu / Fang Kong / Jianan Chen / Baoliang Lan / Guodong He / Kaixuan Gao / Lili Cheng / Xiaoou Sun / Chuangye Yan / Ligong Chen / Xiangyu Liu /
PubMed AbstractThe 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 linksCell Discov / PubMed:38485705 / PubMed Central
MethodsEM (single particle)
Resolution2.98 - 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*YM / Metformin

ChemComp-SNL:
SPIRONOLACTONE / medication*YM / Spironolactone

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / SLC / transporter

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