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- EMDB-14725: Structure of human OCT3 in complex with inhibitor Corticosterone -

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Basic information

Entry
Database: EMDB / ID: EMD-14725
TitleStructure of human OCT3 in complex with inhibitor Corticosterone
Map data
Sample
  • Complex: human OCT3 in complex with inhibitor Corticosterone
    • Protein or peptide: Solute carrier family 22 member 3
  • Ligand: CORTICOSTERONE
Function / homology
Function and homology information


histamine transport / epinephrine uptake / histamine metabolic process / norepinephrine uptake / monocarboxylic acid transport / histamine uptake / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / quaternary ammonium group transport ...histamine transport / epinephrine uptake / histamine metabolic process / norepinephrine uptake / monocarboxylic acid transport / histamine uptake / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / quaternary ammonium group transport / epinephrine transport / purine-containing compound transmembrane transport / spermidine transport / organic cation transport / Organic cation transport / organic cation transmembrane transporter activity / dopamine uptake / regulation of appetite / norepinephrine transport / : / neurotransmitter transmembrane transporter activity / monoamine transmembrane transporter activity / serotonin uptake / toxin transmembrane transporter activity / monoamine transport / Abacavir transmembrane transport / dopamine transport / organic anion transport / organic anion transmembrane transporter activity / neurotransmitter transport / nuclear outer membrane / xenobiotic transport / transport across blood-brain barrier / endomembrane system / monoatomic ion transport / 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. / Sugar transporter, conserved site / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 22 member 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.67 Å
AuthorsKhanppnavar B / Korkhov V
Funding support Switzerland, 1 items
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, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateApr 19, 2023-
Current statusApr 19, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14725.png

Downloads & links

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Map

FileDownload / File: emd_14725.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.66 Å
Density
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.03045895 - 0.040650886
Average (Standard dev.)3.7475424e-05 (±0.0009262495)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 231.00002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half1

Fileemd_14725_half_map_1.map
Annotationhalf1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half2

Fileemd_14725_half_map_2.map
Annotationhalf2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human OCT3 in complex with inhibitor Corticosterone

EntireName: human OCT3 in complex with inhibitor Corticosterone
Components
  • Complex: human OCT3 in complex with inhibitor Corticosterone
    • Protein or peptide: Solute carrier family 22 member 3
  • Ligand: CORTICOSTERONE

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Supramolecule #1: human OCT3 in complex with inhibitor Corticosterone

SupramoleculeName: human OCT3 in complex with inhibitor Corticosterone / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier family 22 member 3

MacromoleculeName: Solute carrier family 22 member 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.332836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPSFDEALQR VGEFGRFQRR VFLLLCLTGV TFAFLFVGVV FLGTQPDHYW CRGPSAAALA ERCGWSPEEE WNRTAPASRG PEPPERRGR CQRYLLEAAN DSASATSALS CADPLAAFPN RSAPLVPCRG GWRYAQAHST IVSEFDLVCV NAWMLDLTQA I LNLGFLTG ...String:
MPSFDEALQR VGEFGRFQRR VFLLLCLTGV TFAFLFVGVV FLGTQPDHYW CRGPSAAALA ERCGWSPEEE WNRTAPASRG PEPPERRGR CQRYLLEAAN DSASATSALS CADPLAAFPN RSAPLVPCRG GWRYAQAHST IVSEFDLVCV NAWMLDLTQA I LNLGFLTG AFTLGYAADR YGRIVIYLLS CLGVGVTGVV VAFAPNFPVF VIFRFLQGVF GKGTWMTCYV IVTEIVGSKQ RR IVGIVIQ MFFTLGIIIL PGIAYFIPNW QGIQLAITLP SFLFLLYYWV VPESPRWLIT RKKGDKALQI LRRIAKCNGK YLS SNYSEI TVTDEEVSNP SFLDLVRTPQ MRKCTLILMF AWFTSAVVYQ GLVMRLGIIG GNLYIDFFIS GVVELPGALL ILLT IERLG RRLPFAASNI VAGVACLVTA FLPEGIAWLR TTVATLGRLG ITMAFEIVYL VNSELYPTTL RNFGVSLCSG LCDFG GIIA PFLLFRLAAV WLELPLIIFG ILASICGGLV MLLPETKGIA LPETVDDVEK LGSPHSCKCG RNKKTPVSRS HL

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Macromolecule #2: CORTICOSTERONE

MacromoleculeName: CORTICOSTERONE / type: ligand / ID: 2 / Number of copies: 1 / Formula: C0R
Molecular weightTheoretical: 346.461 Da
Chemical component information

ChemComp-C0R:
CORTICOSTERONE / hormone*YM / Corticosterone

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.5 µm
Image recording#0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #0 - Average electron dose: 49.0 e/Å2 / #0 - Details: Dataset 1 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Average electron dose: 51.0 e/Å2 / #1 - Details: Dataset 2 / #2 - Image recording ID: 3 / #2 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #2 - Average electron dose: 61.0 e/Å2 / #2 - Details: Dataset 3
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

14716

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.67 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139149
Image recording ID1
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7zh0


Chain - Chain ID: A
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 95
Output model

PDB-7zh6:
Structure of human OCT3 in complex with inhibitor Corticosterone

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