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- PDB-8ju0: hOCT1 in complex with spironolactone in inward facing occluded co... -

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Basic information

Entry
Database: PDB / ID: 8ju0
TitlehOCT1 in complex with spironolactone in inward facing occluded conformation
ComponentsSolute carrier family 22 member 1
KeywordsMEMBRANE PROTEIN / SLC / transporter
Function / homology
Function and homology information


secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity ...secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / organic cation transport / epinephrine transport / purine-containing compound transmembrane transport / quaternary ammonium group transport / spermidine transport / Organic cation transport / organic cation transmembrane transporter activity / thiamine transmembrane transport / thiamine transmembrane transporter activity / putrescine transport / thiamine transport / dopamine uptake / metanephric proximal tubule development / prostaglandin transport / toxin transmembrane transporter activity / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / Abacavir transmembrane transport / establishment or maintenance of transmembrane electrochemical gradient / dopamine:sodium symporter activity / norepinephrine transport / Norepinephrine Neurotransmitter Release Cycle / serotonin uptake / neurotransmitter transmembrane transporter activity / organic anion transmembrane transporter activity / dopamine transport / xenobiotic transport across blood-brain barrier / Neurotransmitter clearance / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / Ciprofloxacin ADME / cellular detoxification / neurotransmitter transport / xenobiotic transport / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / lateral plasma membrane / xenobiotic metabolic process / basal plasma membrane / presynapse / basolateral plasma membrane / apical plasma membrane / identical protein binding / membrane / plasma membrane
Similarity search - Function
Organic cation transport protein/SVOP / Sugar transport proteins signature 1. / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Sugar transporter, conserved site / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
SPIRONOLACTONE / Solute carrier family 22 member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsZhang, S. / Zhu, A. / Kong, F. / Chen, J. / Lan, B. / He, G. / Gao, K. / Cheng, L. / Yan, C. / Chen, L. / Liu, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122041 China
CitationJournal: Cell Discov / Year: 2024
Title: Structural insights into human organic cation transporter 1 transport and inhibition.
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 /
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.
History
DepositionJun 23, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,9862
Polymers62,5691
Non-polymers4171
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Solute carrier family 22 member 1 / Organic cation transporter 1 / hOCT1


Mass: 62569.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A1, OCT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O15245
#2: Chemical ChemComp-SNL / SPIRONOLACTONE / 17-HYDROXY-7ALPHA-MERCAPTO-3-OXO-17ALPHA-PREGN-4-ENE-21- CARBOXYLIC ACID / GAMMA-LACTONE ACETATE


Mass: 416.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32O4S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human organic cation transporter in compelx wtih spironolactone in inward facing occludded conformation
Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 602445 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033282
ELECTRON MICROSCOPYf_angle_d0.5494494
ELECTRON MICROSCOPYf_dihedral_angle_d5.924467
ELECTRON MICROSCOPYf_chiral_restr0.037536
ELECTRON MICROSCOPYf_plane_restr0.004552

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