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- EMDB-51624: Human monocarboxylate transporter 8 D424N mutant -

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Basic information

Entry
Database: EMDB / ID: EMD-51624
TitleHuman monocarboxylate transporter 8 D424N mutant
Map dataHuman monocarboxylate transporter 8 D424N
Sample
  • Complex: Monocarboxylate transporter 8 D424N mutant
    • Protein or peptide: Monocarboxylate transporter 8
Keywordsthyroid / thyroid hormones / transporter / Allan-Herndon-Dudley syndrome / 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 / amino acid import across plasma membrane / thyroid hormone transport / 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 / amino acid import across plasma membrane / thyroid hormone transport / 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: 4.0 Å
AuthorsTassinari M / Coscia F
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)101041298European Union
CitationJournal: Nat Commun / Year: 2025
Title: Molecular mechanism of thyroxine transport by monocarboxylate transporters.
Authors: Matteo Tassinari / Giorgia Tanzi / Francesco Maggiore / Stefan Groeneweg / Ferdy S van Geest / Matthijs E T Freund / Christiaan J Stavast / Irene Boniardi / Sebastiano Pasqualato / W Edward ...Authors: Matteo Tassinari / Giorgia Tanzi / Francesco Maggiore / Stefan Groeneweg / Ferdy S van Geest / Matthijs E T Freund / Christiaan J Stavast / Irene Boniardi / Sebastiano Pasqualato / W Edward Visser / Francesca Coscia /
Abstract: Thyroid hormones (the common name for prohormone thyroxine and the bioactive form triiodothyronine) control major developmental and metabolic processes. Release of thyroid hormones from the thyroid ...Thyroid hormones (the common name for prohormone thyroxine and the bioactive form triiodothyronine) control major developmental and metabolic processes. Release of thyroid hormones from the thyroid gland into the bloodstream and their transport into target cells is facilitated by plasma membrane transporters, including monocarboxylate transporter (MCT)8 and the highly homologous MCT10. However, the molecular mechanism underlying thyroid hormone transport is unknown. The relevance of such transporters is illustrated in patients with MCT8 deficiency, a severe neurodevelopmental and metabolic disorder. Using cryogenic-sample electron microscopy (cryo-EM), we determined the ligand-free and thyroxine-bound human MCT8 structures in the outward-facing state and the thyroxine-bound human MCT10 in the inward-facing state. Our structural analysis revealed a network of conserved gate residues involved in conformational changes upon thyroxine binding, triggering ligand release in the opposite compartment. We then determined the structure of a folded but inactive patient-derived MCT8 mutant, indicating a subtle conformational change which explains its reduced transport activity. Finally, we report a structure of MCT8 bound to its inhibitor silychristin, locked in the outward-facing state, revealing the molecular basis of its action and specificity. Taken together, this study advances mechanistic understanding of normal and disordered thyroid hormone transport.
History
DepositionSep 22, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateJun 11, 2025-
Current statusJun 11, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51624.png

Downloads & links

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Map

FileDownload / File: emd_51624.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman monocarboxylate transporter 8 D424N
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 312 pix.
= 233.376 Å		0.75 Å/pix.
x 312 pix.
= 233.376 Å		0.75 Å/pix.
x 312 pix.
= 233.376 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.748 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.022508804 - 0.06528841
Average (Standard dev.)0.000062159306 (±0.0009350125)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions312312312
Spacing312312312
CellA=B=C: 233.376 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Human monocarboxylate transporter 8 D424N - half 1

Fileemd_51624_half_map_1.map
AnnotationHuman monocarboxylate transporter 8 D424N - half 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human monocarboxylate transporter 8 D424N - half 2

Fileemd_51624_half_map_2.map
AnnotationHuman monocarboxylate transporter 8 D424N - half 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 : Monocarboxylate transporter 8 D424N mutant

EntireName: Monocarboxylate transporter 8 D424N mutant
Components
  • Complex: Monocarboxylate transporter 8 D424N mutant
    • Protein or peptide: Monocarboxylate transporter 8

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Supramolecule #1: Monocarboxylate transporter 8 D424N mutant

SupramoleculeName: Monocarboxylate transporter 8 D424N mutant / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60 KDa

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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: 57.774902 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKA LQSQASEEAK GPWQEADQEQ QEPVGSPEPE SEPEPEPEPE PVPVPPPEPQ PEPQPLPDPA PLPELEFESE RVHEPEPTP TVETRGTARG FQPPEGGFGW VVVFAATWCN GSIFGIHNSV GILYSMLLEE EKEKNRQVEF QAAWVGALAM G MIFFCSPI ...String:
MDYKDDDDKA LQSQASEEAK GPWQEADQEQ QEPVGSPEPE SEPEPEPEPE PVPVPPPEPQ PEPQPLPDPA PLPELEFESE RVHEPEPTP TVETRGTARG FQPPEGGFGW VVVFAATWCN GSIFGIHNSV GILYSMLLEE EKEKNRQVEF QAAWVGALAM G MIFFCSPI VSIFTDRLGC RITATAGAAV AFIGLHTSSF TSSLSLRYFT YGILFGCGCS FAFQPSLVIL GHYFQRRLGL AN GVVSAGS SIFSMSFPFL IRMLGDKIKL AQTFQVLSTF MFVLMLLSLT YRPLLPSSQD TPSKRGVRTL HQRFLAQLRK YFN MRVFRQ RTYRIWAFGI AAAALGYFVP YVHLMKYVEE EFSEIKETWV LLVCIGATSG LGRLVSGHIS DSIPGLKKIY LQVL SFLLL GLMSMMIPLC RDFGGLIVVC LFLGLCNGFF ITIMAPIAFE LVGPMQASQA IGYLLGMMAL PMIAGPPIAG LLRNC FGDY HVAFYFAGVP PIIGAVILFF VPSRLEEELR RRLTEPI

UniProtKB: Monocarboxylate transporter 8

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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

Concentration1.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 mMC8H18N2O4Shepes
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 52344
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 6
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6021


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9gv5:
Human monocarboxylate transporter 8 D424N mutant

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