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- EMDB-40336: Human OCT1 bound to fenoterol in inward-open conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-40336
TitleHuman OCT1 bound to fenoterol in inward-open conformation
Map dataHuman OCT1 bound to fenoterol in inward-open conformation
Sample
  • Complex: Human OCT1
    • Protein or peptide: Solute carrier family 22 member 1
  • Ligand: Fenoterol
Keywordsmembrane protein / MFS / drug transporter / TRANSPORT PROTEIN
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 / 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 transport / organic cation transmembrane transporter activity / putrescine transport / thiamine transport / dopamine uptake / metanephric proximal tubule development / prostaglandin transport / dopamine:sodium symporter activity / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / norepinephrine transport / toxin transmembrane transporter activity / Abacavir transmembrane transport / Norepinephrine Neurotransmitter Release Cycle / neurotransmitter transmembrane transporter activity / serotonin uptake / dopamine transport / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / organic anion transmembrane transporter activity / monoamine transport / establishment or maintenance of transmembrane electrochemical gradient / xenobiotic transport across blood-brain barrier / Neurotransmitter clearance / xenobiotic transport / Ciprofloxacin ADME / neurotransmitter transport / cellular detoxification / 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 / membrane / identical protein binding / 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
Solute carrier family 22 member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsZeng YC / Sobti M / Stewart AG
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP2016308 Australia
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.
Authors: Yi C Zeng / Meghna Sobti / Ada Quinn / Nicola J Smith / Simon H J Brown / Jamie I Vandenberg / Renae M Ryan / Megan L O'Mara / Alastair G Stewart /
Abstract: Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of ...Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.
History
DepositionApr 4, 2023-
Header (metadata) releaseOct 18, 2023-
Map releaseOct 18, 2023-
UpdateOct 25, 2023-
Current statusOct 25, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40336.png

Downloads & links

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Map

FileDownload / File: emd_40336.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman OCT1 bound to fenoterol in inward-open conformation
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.7703761 - 1.0322969
Average (Standard dev.)0.0003656911 (±0.016070904)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_40336_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_40336_half_map_2.map
AnnotationHalf Map 2
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 OCT1

EntireName: Human OCT1
Components
  • Complex: Human OCT1
    • Protein or peptide: Solute carrier family 22 member 1
  • Ligand: Fenoterol

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Supramolecule #1: Human OCT1

SupramoleculeName: Human OCT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier family 22 member 1

MacromoleculeName: Solute carrier family 22 member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.200664 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY ...String:
MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY FADRFGRKLC LLGTVLVNAV SGVLMAFSPN YMSMLLFRLL QGLVSKGNWM AGYTLITEFV GSGSRRTVAI MY QMAFTVG LVALTGLAYA LPHWRWLQLA VSLPTFLFLL YYWCVPESPR WLLSQKRNTE AIKIMDHIAQ KNGKLPPADL KML SLEEDV TEKLSPSFAD LFRTPRLRKR TFILMYLWFT DSVLYQGLIL HMGATSGNLY LDFLYSALVE IPGAFIALIT IDRV GRIYP MAMSNLLAGA ACLVMIFISP DLHWLNIIIM CVGRMGITIA IQMICLVNAE LYPTFVRNLG VMVCSSLCDI GGIIT PFIV FRLREVWQAL PLILFAVLGL LAAGVTLLLP ETKGVALPET MKDAENLGRK AKPKENTIYL KVQTSEPSGT

UniProtKB: Solute carrier family 22 member 1

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Macromolecule #2: Fenoterol

MacromoleculeName: Fenoterol / type: ligand / ID: 2 / Number of copies: 1 / Formula: ZVJ
Molecular weightTheoretical: 303.353 Da
Chemical component information

ChemComp-ZVJ:
Fenoterol

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 88.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 849183
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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