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Structure paper

TitleMolecular basis of polyspecific drug and xenobiotic recognition by OCT1 and OCT2.
Journal, issue, pagesNat Struct Mol Biol, Vol. 30, Issue 7, Page 1001-1011, Year 2023
Publish dateJun 8, 2023
AuthorsYang Suo / Nicholas J Wright / Hugo Guterres / Justin G Fedor / Kevin John Butay / Mario J Borgnia / Wonpil Im / Seok-Yong Lee /
PubMed AbstractA 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 ...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.
External linksNat Struct Mol Biol / PubMed:37291422 / PubMed Central
MethodsEM (single particle)
Resolution3.45 - 3.77 Å
Structure data

28586

8et6

EMDB-28586, PDB-8et6:
Cryo-EM structure of the organic cation transporter 1 in the apo state
Method: EM (single particle) / Resolution: 3.57 Å

28587

8et7

EMDB-28587, PDB-8et7:
Cryo-EM structure of the organic cation transporter 1 in complex with diphenhydramine
Method: EM (single particle) / Resolution: 3.77 Å

28588

8et8

EMDB-28588, PDB-8et8:
Cryo-EM structure of the organic cation transporter 1 in complex with verapamil
Method: EM (single particle) / Resolution: 3.45 Å

28589

8et9

EMDB-28589, PDB-8et9:
Cryo-EM structure of the organic cation transporter 2 in complex with 1-methyl-4-phenylpyridinium
Method: EM (single particle) / Resolution: 3.61 Å

Chemicals

ChemComp-2PM:
N-[2-(BENZHYDRYLOXY)ETHYL]-N,N-DIMETHYLAMINE / Diphenhydramine

ChemComp-4YH:
(2S)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile

ChemComp-WRF:
1-methyl-4-phenylpyridin-1-ium

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / organic cation / transport / membrane protein / Cation

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