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- EMDB-50523: Human monocarboxylate transporter 8 bound to thyroxine -

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Basic information

Entry
Database: EMDB / ID: EMD-50523
TitleHuman monocarboxylate transporter 8 bound to thyroxine
Map dataMCT8 bound to T4
Sample
  • Complex: ALFA-tag nanobody bound to MCT8 in complex to T4
    • Protein or peptide: Monocarboxylate transporter 8
    • Protein or peptide: ALFA-tag nanobody
  • Ligand: 3,5,3',5'-TETRAIODO-L-THYRONINE
KeywordsThyroid / Hormones / SLC16A2 / Transporter / Thyroxine / 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) / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsCoscia F / Tassinari M
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)101041298 THYROMOLEuropean 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
DepositionJun 3, 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_50523.png

Downloads & links

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Map

FileDownload / File: emd_50523.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMCT8 bound to T4
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-0.028397575 - 0.05736263
Average (Standard dev.)0.00006162775 (±0.0010853074)
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: MCT8 bound to T4 - Half 1

Fileemd_50523_half_map_1.map
AnnotationMCT8 bound to T4 - Half 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: MCT8 bound to T4 - Half 2

Fileemd_50523_half_map_2.map
AnnotationMCT8 bound to T4 - 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 : ALFA-tag nanobody bound to MCT8 in complex to T4

EntireName: ALFA-tag nanobody bound to MCT8 in complex to T4
Components
  • Complex: ALFA-tag nanobody bound to MCT8 in complex to T4
    • Protein or peptide: Monocarboxylate transporter 8
    • Protein or peptide: ALFA-tag nanobody
  • Ligand: 3,5,3',5'-TETRAIODO-L-THYRONINE

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Supramolecule #1: ALFA-tag nanobody bound to MCT8 in complex to T4

SupramoleculeName: ALFA-tag nanobody bound to MCT8 in complex to T4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71 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: 57.775887 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 LFLGLCDGFF ITIMAPIAFE LVGPMQASQA IGYLLGMMAL PMIAGPPIAG LLRNC FGDY HVAFYFAGVP PIIGAVILFF VPSRLEEELR RRLTEPI

UniProtKB: Monocarboxylate transporter 8

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Macromolecule #2: ALFA-tag nanobody

MacromoleculeName: ALFA-tag nanobody / type: protein_or_peptide / ID: 2
Details: Nanobody anti-ALFA tag as in the PDB 6I2G, with N-ter TEV cleavage site.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 13.599183 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
GSEVQLQESG GGLVQPGGSL RLSCTASGVT ISALNAMAMG WYRQAPGERR VMVAAVSERG NAMYRESVQG RFTVTRDFTN KMVSLQMDN LKPEDTAVYY CHVLEDRVDS FHDYWGQGTQ VTVSS

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

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

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

Concentration0.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonicHEPES
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279.15 K / Instrument: FEI VITROBOT MARK IV
DetailsMCT8 stabilised in amphipols PMAL-C8

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 22504 / 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 reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 173884
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0) / Software - details: Blush
FSC plot (resolution estimation)

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