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- EMDB-47274: Cryo-EM structure of human MCT8 in complex with thyroid hormone T3 -

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Basic information

Entry
Database: EMDB / ID: EMD-47274
TitleCryo-EM structure of human MCT8 in complex with thyroid hormone T3
Map data
Sample
  • Complex: human MCT8 in complex with thyroid hormone T3
    • Protein or peptide: Monocarboxylate transporter 8
  • Ligand: 3,5,3'TRIIODOTHYRONINE
KeywordsSLC transporter / thyroid hormone / TRANSPORT PROTEIN
Function / homology
Function and homology information


thyroid-stimulating hormone secretion / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / Transport of organic anions / thyroid hormone metabolic process / negative regulation of neural precursor cell proliferation / thyroid hormone transmembrane transporter activity / thyroid hormone transport / amino acid import across plasma membrane / amino acid transmembrane transporter activity ...thyroid-stimulating hormone secretion / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / Transport of organic anions / thyroid hormone metabolic process / negative regulation of neural precursor cell proliferation / thyroid hormone transmembrane transporter activity / thyroid hormone transport / amino acid import across plasma membrane / amino acid transmembrane transporter activity / thyroid hormone generation / amino acid metabolic process / transport across blood-brain barrier / apical plasma membrane / identical protein binding / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Monocarboxylate transporter 8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsGe Y / Dou T / 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
DepositionOct 10, 2024-
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_47274.png

Downloads & links

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Map

FileDownload / File: emd_47274.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.125
Minimum - Maximum-0.6132982 - 0.90287906
Average (Standard dev.)0.000711194 (±0.013775083)
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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Mask #1

Fileemd_47274_msk_1.map
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Half map: #2

Fileemd_47274_half_map_1.map
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Half map: #1

Fileemd_47274_half_map_2.map
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Sample components

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Entire : human MCT8 in complex with thyroid hormone T3

EntireName: human MCT8 in complex with thyroid hormone T3
Components
  • Complex: human MCT8 in complex with thyroid hormone T3
    • Protein or peptide: Monocarboxylate transporter 8
  • Ligand: 3,5,3'TRIIODOTHYRONINE

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Supramolecule #1: human MCT8 in complex with thyroid hormone T3

SupramoleculeName: human MCT8 in complex with thyroid hormone T3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Monocarboxylate transporter 8

MacromoleculeName: Monocarboxylate transporter 8 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 63.329227 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MALQSQASEE AKGPWQEADQ EQQEPVGSPE PESEPEPEPE PEPVPVPPPE PQPEPQPLPD PAPLPELEFE SERVHEPEPT PTVETRGTA RGFQPPEGGF GWVVVFAATW CNGSIFGIHN SVGILYSMLL EEEKEKNRQV EFQAAWVGAL AMGMIFFCSP I VSIFTDRL ...String:
MALQSQASEE AKGPWQEADQ EQQEPVGSPE PESEPEPEPE PEPVPVPPPE PQPEPQPLPD PAPLPELEFE SERVHEPEPT PTVETRGTA RGFQPPEGGF GWVVVFAATW CNGSIFGIHN SVGILYSMLL EEEKEKNRQV EFQAAWVGAL AMGMIFFCSP I VSIFTDRL GCRITATAGA AVAFIGLHTS SFTSSLSLRY FTYGILFGCG CSFAFQPSLV ILGHYFQRRL GLANGVVSAG SS IFSMSFP FLIRMLGDKI KLAQTFQVLS TFMFVLMLLS LTYRPLLPSS QDTPSKRGVR TLHQRFLAQL RKYFNMRVFR QRT YRIWAF GIAAAALGYF VPYVHLMKYV EEEFSEIKET WVLLVCIGAT SGLGRLVSGH ISDSIPGLKK IYLQVLSFLL LGLM SMMIP LCRDFGGLIV VCLFLGLCDG FFITIMAPIA FELVGPMQAS QAIGYLLGMM ALPMIAGPPI AGLLRNCFGD YHVAF YFAG VPPIIGAVIL FFVPLMHQRM FKKEQRDSSK DKMLAPDPDP NGELLPGSPN PEEPIAAALE VLFQGPGAAE DQVDPR LID GKHHHHHHHH

UniProtKB: Monocarboxylate transporter 8

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Macromolecule #2: 3,5,3'TRIIODOTHYRONINE

MacromoleculeName: 3,5,3'TRIIODOTHYRONINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: T3
Molecular weightTheoretical: 650.973 Da
Chemical component information

ChemComp-T3:
3,5,3'TRIIODOTHYRONINE / hormone*YM

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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 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 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 AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 59661
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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