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- EMDB-51559: Human monocarboxylate transporter 10 bound to L-thyroxine -

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Basic information

Entry
Database: EMDB / ID: EMD-51559
TitleHuman monocarboxylate transporter 10 bound to L-thyroxine
Map dataMonocarboxylate transporter 10 bound to L-thyroxine
Sample
  • Complex: Monocarboxylate transporter 10 bound to anti-alfa nanobody and L-thyroxine
    • Protein or peptide: Monocarboxylate transporter 10
  • Ligand: 3,5,3',5'-TETRAIODO-L-THYRONINE
KeywordsL-thyroxine / Thyroid / Transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


L-tyrosine transmembrane transporter activity / L-phenylalanine transmembrane transporter activity / aromatic amino acid transport / thyroid-stimulating hormone secretion / L-tryptophan transmembrane transporter activity / aromatic amino acid transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity ...L-tyrosine transmembrane transporter activity / L-phenylalanine transmembrane transporter activity / aromatic amino acid transport / thyroid-stimulating hormone secretion / L-tryptophan transmembrane transporter activity / aromatic amino acid transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / thyroid hormone generation / amino acid transport / transmembrane transporter activity / cell junction / basolateral plasma membrane / intracellular membrane-bounded organelle / 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 10
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsCoscia F / Tassinari M
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 16, 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_51559.png

Downloads & links

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Map

FileDownload / File: emd_51559.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMonocarboxylate transporter 10 bound to L-thyroxine
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: 0.02
Minimum - Maximum-0.050612003 - 0.0867043
Average (Standard dev.)0.000068021756 (±0.0014825454)
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: Monocarboxylate transporter 10 bound to L-thyroxine - Half1

Fileemd_51559_half_map_1.map
AnnotationMonocarboxylate transporter 10 bound to L-thyroxine - Half1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Monocarboxylate transporter 10 bound to L-thyroxine - Half2

Fileemd_51559_half_map_2.map
AnnotationMonocarboxylate transporter 10 bound to L-thyroxine - Half2
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 10 bound to anti-alfa nanobody and L-...

EntireName: Monocarboxylate transporter 10 bound to anti-alfa nanobody and L-thyroxine
Components
  • Complex: Monocarboxylate transporter 10 bound to anti-alfa nanobody and L-thyroxine
    • Protein or peptide: Monocarboxylate transporter 10
  • Ligand: 3,5,3',5'-TETRAIODO-L-THYRONINE

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Supramolecule #1: Monocarboxylate transporter 10 bound to anti-alfa nanobody and L-...

SupramoleculeName: Monocarboxylate transporter 10 bound to anti-alfa nanobody and L-thyroxine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50 KDa

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Macromolecule #1: Monocarboxylate transporter 10

MacromoleculeName: Monocarboxylate transporter 10 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.242465 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKM VLSQEEPDSA RGTSEAQPLG PAPTGAAPPP GPGPSDSPEA AVEKVEVELA GPATAEPHEP PEPPEGGWGW LVMLAAMWC NGSVFGIQNA CGVLFVSMLE TFGSKDDDKM VFKTAWVGSL SMGMIFFCCP IVSVFTDLFG CRKTAVVGAA V GFVGLMSS ...String:
MDYKDDDDKM VLSQEEPDSA RGTSEAQPLG PAPTGAAPPP GPGPSDSPEA AVEKVEVELA GPATAEPHEP PEPPEGGWGW LVMLAAMWC NGSVFGIQNA CGVLFVSMLE TFGSKDDDKM VFKTAWVGSL SMGMIFFCCP IVSVFTDLFG CRKTAVVGAA V GFVGLMSS SFVSSIEPLY LTYGIIFACG CSFAYQPSLV ILGHYFKKRL GLVNGIVTAG SSVFTILLPL LLRVLIDSVG LF YTLRVLC IFMFVLFLAG FTYRPLATST KDKESGGSGS SLFSRKKFSP PKKIFNFAIF KVTAYAVWAV GIPLALFGYF VPY VHLMKH VNERFQDEKN KEVVLMCIGV TSGVGRLLFG RIADYVPGVK KVYLQVLSFF FIGLMSMMIP LCSIFGALIA VCLI MGLFD GCFISIMAPI AFELVGAQDV SQAIGFLLGF MSIPMTVGPP IAGLLRDKLG SYDVAFYLAG VPPLIGGAVL CFIPS RLEE ELRRRLTEP

UniProtKB: Monocarboxylate transporter 10

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Macromolecule #2: 3,5,3',5'-TETRAIODO-L-THYRONINE

MacromoleculeName: 3,5,3',5'-TETRAIODO-L-THYRONINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: T44
Molecular weightTheoretical: 776.87 Da
Chemical component information

ChemComp-T44:
3,5,3',5'-TETRAIODO-L-THYRONINE

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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

Concentration0.5 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: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279.15 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 36610 / Average exposure time: 6.5 sec. / 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: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 9500000
CTF correctionSoftware - Name: cryoSPARC / Type: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57707
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 6 / Software - Name: RELION (ver. 5) / Software - details: blush
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: ITasser / Chain - Initial model type: in silico model / Details: model generated from PDB 7YR5
SoftwareName: ISOLDE
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9gsz:
Human monocarboxylate transporter 10 bound to L-thyroxine

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