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- PDB-7zha: Structure of human OCT3 in complex with inhibitor decynium-22 -

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Basic information

Entry
Database: PDB / ID: 7zha
TitleStructure of human OCT3 in complex with inhibitor decynium-22
ComponentsSolute carrier family 22 member 3
KeywordsMEMBRANE PROTEIN / Organic cation transporter / major-facilitator superfamily / SLC22 family / Corticosterone sensitive protein / membrane transport / decynium-22
Function / homology
Function and homology information


histamine transport / epinephrine uptake / histamine metabolic process / 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 ...histamine transport / epinephrine uptake / histamine metabolic process / 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 / SLC-mediated transport of organic cations / : / monocarboxylic acid transport / spermidine transport / regulation of appetite / dopamine uptake / histamine uptake / norepinephrine uptake / toxin transmembrane transporter activity / norepinephrine transport / Abacavir transmembrane transport / neurotransmitter transmembrane transporter activity / serotonin uptake / dopamine transport / monoamine transmembrane transporter activity / organic anion transport / monoamine transport / : / cellular detoxification / xenobiotic transport / neurotransmitter transport / nuclear outer membrane / transport across blood-brain barrier / monoatomic ion transport / endomembrane system / mitochondrial membrane / presynapse / basolateral plasma membrane / apical plasma membrane / neuronal cell body / membrane / plasma membrane
Similarity search - Function
Organic cation transport protein/SVOP / Sugar transport proteins signature 1. / MFS general substrate transporter like domains / Sugar transporter, conserved site / Growth Hormone; Chain: A; / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily ...Organic cation transport protein/SVOP / Sugar transport proteins signature 1. / MFS general substrate transporter like domains / Sugar transporter, conserved site / Growth Hormone; Chain: A; / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
1-ethyl-2-[(1-ethylquinolin-2-yl)methyl]quinoline / Solute carrier family 22 member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsKhanppnavar, B. / Korkhov, V.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation198545 Switzerland
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of organic cation transporter-3 inhibition.
Authors: Basavraj Khanppnavar / Julian Maier / Freja Herborg / Ralph Gradisch / Erika Lazzarin / Dino Luethi / Jae-Won Yang / Chao Qi / Marion Holy / Kathrin Jäntsch / Oliver Kudlacek / Klaus ...Authors: Basavraj Khanppnavar / Julian Maier / Freja Herborg / Ralph Gradisch / Erika Lazzarin / Dino Luethi / Jae-Won Yang / Chao Qi / Marion Holy / Kathrin Jäntsch / Oliver Kudlacek / Klaus Schicker / Thomas Werge / Ulrik Gether / Thomas Stockner / Volodymyr M Korkhov / Harald H Sitte /
Abstract: Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role ...Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.
History
DepositionApr 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
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Revision 1.0Nov 9, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Nov 9, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Nov 9, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Nov 9, 2022Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Apr 19, 2023Group: Database references / Category: citation / citation_author
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Revision 1.2Oct 16, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,6612
Polymers61,3331
Non-polymers3281
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area23340 Å2

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Components

#1: Protein Solute carrier family 22 member 3 / Extraneuronal monoamine transporter / EMT / Organic cation transporter 3


Mass: 61332.836 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A3, EMTH, OCT3 / Production host: Homo sapiens (human) / References: UniProt: O75751
#2: Chemical ChemComp-JDW / 1-ethyl-2-[(1-ethylquinolin-2-yl)methyl]quinoline


Mass: 328.450 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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 OCT3 reconstituted in lipid nanodisc and in complex with inhibitor decynium-22
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector modelDetails
1151GATAN K3 BIOQUANTUM (6k x 4k)Dataset 1
2149GATAN K3 BIOQUANTUM (6k x 4k)Dataset 2 & 3

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130654 / Symmetry type: POINT
Atomic model buildingB value: 100 / Protocol: AB INITIO MODEL / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044458
ELECTRON MICROSCOPYf_angle_d0.7036073
ELECTRON MICROSCOPYf_dihedral_angle_d4.472609
ELECTRON MICROSCOPYf_chiral_restr0.045696
ELECTRON MICROSCOPYf_plane_restr0.005760

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