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- EMDB-36655: hOCT1 in complex with nb5660 in inward facing fully open conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-36655
TitlehOCT1 in complex with nb5660 in inward facing fully open conformation
Map data
Sample
  • Complex: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation
    • Protein or peptide: Solute carrier family 22 member 1
    • Protein or peptide: nanobody 56
KeywordsSLC / transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 / organic cation transport / epinephrine 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 / organic cation transport / epinephrine transport / purine-containing compound transmembrane transport / quaternary ammonium group transport / acetylcholine transmembrane transporter activity / spermidine transport / Organic cation transport / organic cation transmembrane transporter activity / putrescine transport / dopamine uptake / metanephric proximal tubule development / thiamine transmembrane transport / thiamine transmembrane transporter activity / thiamine transport / prostaglandin transport / toxin transmembrane transporter activity / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / dopamine:sodium symporter activity / norepinephrine transport / Abacavir transmembrane transport / Norepinephrine Neurotransmitter Release Cycle / neurotransmitter transmembrane transporter activity / serotonin uptake / establishment or maintenance of transmembrane electrochemical gradient / dopamine transport / Neurotransmitter clearance / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / Ciprofloxacin ADME / cellular detoxification / neurotransmitter transport / xenobiotic transport / xenobiotic transmembrane transporter activity / lateral plasma membrane / 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) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsZhang S / Zhu A / Kong F / Chen J / Lan B / He G / Gao K / Cheng L / Yan C / Chen L / Liu X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122041 China
CitationJournal: Cell Discov / Year: 2024
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
DepositionJun 22, 2023-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36655.png

Downloads & links

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Map

FileDownload / File: emd_36655.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.75
Minimum - Maximum-7.214002 - 9.10426
Average (Standard dev.)-0.0040245606 (±0.17421655)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36655_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_36655_half_map_2.map
Projections & Slices
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Sample components

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Entire : human organic cation transporter in compelx wtih nb5660 in inward...

EntireName: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation
Components
  • Complex: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation
    • Protein or peptide: Solute carrier family 22 member 1
    • Protein or peptide: nanobody 56

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Supramolecule #1: human organic cation transporter in compelx wtih nb5660 in inward...

SupramoleculeName: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: 62.569164 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 EDQVDP RLI DGK

UniProtKB: Solute carrier family 22 member 1

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Macromolecule #2: nanobody 56

MacromoleculeName: nanobody 56 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.421984 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQAGGSLRL SCAASGTIFY YEIMGWYRQA PGKEREFVAT IDQGGITNYA DSVKGRFTIS RDNAKNTVYL QMNSLKPED TAVYYCAVPD VFVGRGWDYL IYWGQGTQVT VSSGSHHHHH H

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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
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.1 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 110551
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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