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- PDB-8jtx: hOCT1 in complex with nb5660 in inward facing fully open conformation -
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Open data
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Basic information
Entry | Database: PDB / ID: 8jtx | ||||||
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Title | hOCT1 in complex with nb5660 in inward facing fully open conformation | ||||||
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![]() | MEMBRANE PROTEIN / SLC / transporter | ||||||
Function / homology | ![]() 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 / quaternary ammonium group transport / epinephrine transport / thiamine transmembrane transport / purine-containing compound transmembrane transport / spermidine transport / thiamine transmembrane transporter activity / Organic cation transport / organic cation transmembrane transporter activity / putrescine transport / thiamine transport / dopamine uptake / metanephric proximal tubule development / prostaglandin transport / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / toxin transmembrane transporter activity / Abacavir transmembrane transport / Norepinephrine Neurotransmitter Release Cycle / dopamine:sodium symporter activity / norepinephrine transport / serotonin uptake / neurotransmitter transmembrane transporter activity / dopamine transport / establishment or maintenance of transmembrane electrochemical gradient / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / monoamine transmembrane transporter activity / Neurotransmitter clearance / Na+/Cl- dependent neurotransmitter transporters / monoamine transport / Ciprofloxacin ADME / xenobiotic transport / cellular detoxification / neurotransmitter transport / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / lateral plasma membrane / basal plasma membrane / xenobiotic metabolic process / presynapse / basolateral plasma membrane / apical plasma membrane / identical protein binding / membrane / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.28 Å | ||||||
![]() | Zhang, S. / Zhu, A. / Kong, F. / Chen, J. / Lan, B. / He, G. / Gao, K. / Cheng, L. / Yan, C. / Chen, L. / Liu, X. | ||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 119.7 KB | Display | ![]() |
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PDB format | ![]() | 89.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 36655MC ![]() 8jtsC ![]() 8jttC ![]() 8jtvC ![]() 8jtwC ![]() 8jtyC ![]() 8jtzC ![]() 8ju0C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 62569.164 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Antibody | Mass: 14421.984 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Microscopy | Model: FEI TITAN |
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Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1100 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
CTF correction | Type: NONE | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 110551 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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