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- EMDB-48553: Cryo-EM structure of human OATP1C1 F240A mutant in complex with e... -

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Basic information

Entry
Database: EMDB / ID: EMD-48553
TitleCryo-EM structure of human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
Map data
Sample
  • Complex: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
    • Protein or peptide: Solute carrier organic anion transporter family member 1C1
  • Ligand: ESTRONE BETA-D-GLUCURONIDE
KeywordsSLC transporter / E1G / TRANSPORT PROTEIN
Function / homology
Function and homology information


positive regulation of thyroid hormone generation / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / organic anion transmembrane transporter activity / bile acid transmembrane transporter activity / bile acid and bile salt transport / transport across blood-brain barrier ...positive regulation of thyroid hormone generation / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / organic anion transmembrane transporter activity / bile acid transmembrane transporter activity / bile acid and bile salt transport / transport across blood-brain barrier / monoatomic ion transport / transmembrane transport / basolateral plasma membrane / plasma membrane
Similarity search - Function
Organic anion transporter polypeptide / Organic Anion Transporter Polypeptide (OATP) family / Kazal-type serine protease inhibitor domain / Kazal domain superfamily / Kazal domain / Kazal domain profile. / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier organic anion transporter family member 1C1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsGe Y / Yadav GP / Jiang J / Huang P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM150878 United States
CitationJournal: Cell / Year: 2025
Title: Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1.
Authors: Yunhui Ge / Tongyi Dou / Thu Uyen Nguyen / Gaya P Yadav / Theodore G Wensel / Jiansen Jiang / Pengxiang Huang /
Abstract: Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones ...Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones across the blood-brain barrier and into the central nervous system. Mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), an X-linked birth defect characterized by neurodevelopmental impairments and peripheral hyperthyroidism, whereas OATP1C1 deficiency is linked to brain hypometabolism and progressive neurodegeneration. Here, we report cryoelectron microscopy (cryo-EM) structures of MCT8 and OATP1C1 bound with the active thyroid hormone triiodothyronine (T3) and the prohormone thyroxine (T4) at 2.9 and 2.3 Å resolutions, respectively. Combined with functional studies, we elucidate their distinct thyroid hormone recognition and transport mechanisms and explain disease mutations. Although extracellular allosteric sites are not a common feature of SLC transporters, we identify one in OATP1C1. Collectively, these findings illuminate key aspects of thyroid hormone transport, a fundamental process in development and disease.
History
DepositionJan 7, 2025-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48553.png

Downloads & links

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Map

FileDownload / File: emd_48553.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 209.92 Å		0.82 Å/pix.
x 256 pix.
= 209.92 Å		0.82 Å/pix.
x 256 pix.
= 209.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0163
Minimum - Maximum-0.071364105 - 0.11849991
Average (Standard dev.)-0.000056554843 (±0.0025847228)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 209.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48553_msk_1.map
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Half map: #1

Fileemd_48553_half_map_1.map
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Half map: #2

Fileemd_48553_half_map_2.map
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Sample components

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Entire : human OATP1C1 F240A mutant in complex with estrone 3-glucuronide

EntireName: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
Components
  • Complex: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
    • Protein or peptide: Solute carrier organic anion transporter family member 1C1
  • Ligand: ESTRONE BETA-D-GLUCURONIDE

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Supramolecule #1: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide

SupramoleculeName: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier organic anion transporter family member 1C1

MacromoleculeName: Solute carrier organic anion transporter family member 1C1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 82.463227 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDTSSKENIQ LFCKTSVQPV GRPSFKTEYP SSEEKQPCCG ELKVFLCALS FVYFAKALAE GYLKSTITQI ERRFDIPSSL VGVIDGSFE IGNLLVITFV SYFGAKLHRP KIIGAGCVIM GVGTLLIAMP QFFMEQYKYE RYSPSSNSTL SISPCLLESS S QLPVSVME ...String:
MDTSSKENIQ LFCKTSVQPV GRPSFKTEYP SSEEKQPCCG ELKVFLCALS FVYFAKALAE GYLKSTITQI ERRFDIPSSL VGVIDGSFE IGNLLVITFV SYFGAKLHRP KIIGAGCVIM GVGTLLIAMP QFFMEQYKYE RYSPSSNSTL SISPCLLESS S QLPVSVME KSKSKISNEC EVDTSSSMWI YVFLGNLLRG IGETPIQPLG IAYLDDFASE DNAAFYIGCV QTVAIIGPIF GA LLGSLCA KLYVDIGFVN LDHITITPKD PQWVGAWWLG YLIAGIISLL AAVPFWYLPK SLPRSQSRED SNSSSEKSKF IID DHTDYQ TPQGENAKIM EMARDFLPSL KNLFGNPVYF LYLCTSTVQF NSLFGMVTYK PKYIEQQYGQ SSSRANFVIG LINI PAVAL GIFSGGIVMK KFRISVCGAA KLYLGSSVFG YLLFLSLFAL GCENSDVAGL TVSYQGTKPV SYHERALFSD CNSRC KCSE TKWEPMCGEN GITYVSACLA GCQTSNRSGK NIIFYNCTCV GIAASKSGNS SGIVGRCQKD NGCPQMFLYF LVISVI TSY TLSLGGIPGY ILLLRCIKPQ LKSFALGIYT LAIRVLAGIP APVYFGVLID TSCLKWGFKR CGSRGSCRLY DSNVFRH IY LGLTVILGTV SILLSIAVLF ILKKNYVSKH RSFITKRERT MVSTRFQKEN YTTSDHLLQP NYWPGKETQL AAALEVLF Q GPGAAEDQVD PRLIDGKHHH HHHHH

UniProtKB: Solute carrier organic anion transporter family member 1C1

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Macromolecule #2: ESTRONE BETA-D-GLUCURONIDE

MacromoleculeName: ESTRONE BETA-D-GLUCURONIDE / type: ligand / ID: 2 / Number of copies: 1 / Formula: E3G
Molecular weightTheoretical: 446.49 Da
Chemical component information

ChemComp-E3G:
ESTRONE BETA-D-GLUCURONIDE

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.83 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52355
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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