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- EMDB-40335: Human OCT1 bound to diltiazem in inward-open conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-40335
TitleHuman OCT1 bound to diltiazem in inward-open conformation
Map dataHuman OCT1 bound to diltiazem in inward-open conformation
Sample
  • Complex: Human OCT1
    • Protein or peptide: Solute carrier family 22 member 1
  • Ligand: Diltiazem
Keywordsmembrane protein / MFS / drug transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


acetylcholine transport / (R)-carnitine transmembrane transporter activity / O-acyl-L-carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / epinephrine transport / purine-containing compound transmembrane transport / putrescine transmembrane transporter activity ...acetylcholine transport / (R)-carnitine transmembrane transporter activity / O-acyl-L-carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / epinephrine transport / purine-containing compound transmembrane transport / putrescine transmembrane transporter activity / quaternary ammonium group transport / SLC-mediated transport of organic cations / acetylcholine transmembrane transporter activity / organic cation transport / spermidine transport / : / dopamine uptake / putrescine transport / thiamine transmembrane transport / thiamine transmembrane transporter activity / thiamine transport / norepinephrine:sodium symporter activity / metanephric proximal tubule development / toxin transmembrane transporter activity / norepinephrine transport / dopamine:sodium symporter activity / prostaglandin transport / Norepinephrine Neurotransmitter Release Cycle / Abacavir transmembrane transport / prostaglandin transmembrane transporter activity / neurotransmitter transmembrane transporter activity / serotonin uptake / establishment or maintenance of transmembrane electrochemical gradient / dopamine transport / Neurotransmitter clearance / xenobiotic transport across blood-brain barrier / monoamine transmembrane transporter activity / monoamine transport / : / Ciprofloxacin ADME / SLC-mediated transport of neurotransmitters / cellular detoxification / xenobiotic transport / neurotransmitter transport / lateral plasma membrane / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / 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. / Sugar transporter, conserved site / Major facilitator, sugar transporter-like / Sugar (and other) transporter / 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: 3.36 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-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40335.png

Downloads & links

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Map

FileDownload / File: emd_40335.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman OCT1 bound to diltiazem in inward-open conformation
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 256 pix.
= 215.04 Å		0.84 Å/pix.
x 256 pix.
= 215.04 Å		0.84 Å/pix.
x 256 pix.
= 215.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.123
Minimum - Maximum-0.9613441 - 1.0949674
Average (Standard dev.)-0.00010023978 (±0.01847365)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 215.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_40335_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_40335_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: Diltiazem

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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: 59.167422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KQAFLILCLL SAAFAPICVG IVFLGFTPDH HCQSPGVAEL SQRCGWSPAE ELNYTVPGLG PAGEAFLGQC RRYEVDWNQS ALSCVDPLA SLATNRSHLP LGPCQDGWVY DTPGSSIVTE FNLVCADSWK LDLFQSCLNA GFLFGSLGVG YFADRFGRKL C LLGTVLVN ...String:
KQAFLILCLL SAAFAPICVG IVFLGFTPDH HCQSPGVAEL SQRCGWSPAE ELNYTVPGLG PAGEAFLGQC RRYEVDWNQS ALSCVDPLA SLATNRSHLP LGPCQDGWVY DTPGSSIVTE FNLVCADSWK LDLFQSCLNA GFLFGSLGVG YFADRFGRKL C LLGTVLVN AVSGVLMAFS PNYMSMLLFR LLQGLVSKGN WMAGYTLITE FVGSGSRRTV AIMYQMAFTV GLVALTGLAY AL PHWRWLQ LAVSLPTFLF LLYYWCVPES PRWLLSQKRN TEAIKIMDHI AQKNGKLPPA DLKMLSLEED VTEKLSPSFA DLF RTPRLR KRTFILMYLW FTDSVLYQGL ILHMGATSGN LYLDFLYSAL VEIPGAFIAL ITIDRVGRIY PMAMSNLLAG AACL VMIFI SPDLHWLNII IMCVGRMGIT IAIQMICLVN AELYPTFVRN LGVMVCSSLC DIGGIITPFI VFRLREVWQA LPLIL FAVL GLLAAGVTLL LPETKGVALP ETMKDAENLG RKAKPKENTI YLKVQTSEPS GT

UniProtKB: Solute carrier family 22 member 1

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Macromolecule #2: Diltiazem

MacromoleculeName: Diltiazem / type: ligand / ID: 2 / Number of copies: 1 / Formula: C9F
Molecular weightTheoretical: 414.518 Da
Chemical component information

ChemComp-C9F:
Diltiazem

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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

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1345674
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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