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- EMDB-60200: CryoEM structure of Thyroid Hormone Transporter MCT8 bound with s... -

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Basic information

Entry
Database: EMDB / ID: EMD-60200
TitleCryoEM structure of Thyroid Hormone Transporter MCT8 bound with silychristin
Map data
Sample
  • Complex: Thyroid Hormone Transporter MCT8 bound with silychristin
    • Protein or peptide: Monocarboxylate transporter 8
  • Ligand: (2~{R},3~{R})-2-[(2~{S},3~{R})-3-(hydroxymethyl)-2-(3-methoxy-4-oxidanyl-phenyl)-7-oxidanyl-2,3-dihydro-1-benzofuran-5-yl]-3,5,7-tris(oxidanyl)-2,3-dihydrochromen-4-one
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
  • Ligand: water
KeywordsSLC16A2 / MCT8 / MEMBRANE PROTEIN
Function / homology
Function and homology information


thyroid-stimulating hormone secretion / monocarboxylic acid transmembrane transporter activity / monocarboxylic acid transport / Organic anion transport by SLCO transporters / 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 / Organic anion transport by SLCO transporters / 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: 3.06 Å
AuthorsTan J / Xiao Y / Kong F / Zhu A / Qian J / Yan C
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509301 China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into thyroid hormone transporter MCT8.
Authors: Jiaxin Tan / Yuan Xiao / Fang Kong / Jiawei Qian / Angqi Zhu / Chuangye Yan /
Abstract: Thyroid hormones (THs), including T4 (3,5,3',5'-tetraiodo-L-thyronine) and T3 (3,5,3'-triiodo-L-thyronine), play critical roles in regulating tissue development and basal metabolism. Monocarboxylate ...Thyroid hormones (THs), including T4 (3,5,3',5'-tetraiodo-L-thyronine) and T3 (3,5,3'-triiodo-L-thyronine), play critical roles in regulating tissue development and basal metabolism. Monocarboxylate transporter 8 (MCT8) is a key player in TH transport, known for its high specificity and affinity for THs and its direct association with Allan-Herndon-Dudley syndrome (AHDS) caused by pathogenic mutations. In this study, we present the cryo-EM structures of human MCT8 bound to the substrate T3 or the inhibitor silychristin, both in an outward-open conformation at resolutions of 3.0-3.2 Å. MCT8 forms a homodimer with a lipid molecule positioned at the dimerization interface. The carboxyl group of T3 is recognized by Arg371, while its three iodine atoms interact with distinct hydrophobic cavities. Silychristin is also recognized by Arg371, competing with T3 for binding. Complemented by structure-guided biochemical analyses, our research elucidates the mechanisms of substrate recognition and transport, as well as the mode of action of the inhibitor silychristin. These findings may offer insights for developing targeted therapies for TH-related disorders.
History
DepositionMay 16, 2024-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60200.png

Downloads & links

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Map

FileDownload / File: emd_60200.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0979 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-3.4345357 - 5.4110937
Average (Standard dev.)0.012593715 (±0.103722066)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.0624 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60200_msk_1.map
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Half map: #1

Fileemd_60200_half_map_1.map
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Half map: #2

Fileemd_60200_half_map_2.map
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Sample components

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Entire : Thyroid Hormone Transporter MCT8 bound with silychristin

EntireName: Thyroid Hormone Transporter MCT8 bound with silychristin
Components
  • Complex: Thyroid Hormone Transporter MCT8 bound with silychristin
    • Protein or peptide: Monocarboxylate transporter 8
  • Ligand: (2~{R},3~{R})-2-[(2~{S},3~{R})-3-(hydroxymethyl)-2-(3-methoxy-4-oxidanyl-phenyl)-7-oxidanyl-2,3-dihydro-1-benzofuran-5-yl]-3,5,7-tris(oxidanyl)-2,3-dihydrochromen-4-one
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
  • Ligand: water

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Supramolecule #1: Thyroid Hormone Transporter MCT8 bound with silychristin

SupramoleculeName: Thyroid Hormone Transporter MCT8 bound with silychristin
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: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.559059 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 PEEPI

UniProtKB: Monocarboxylate transporter 8

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Macromolecule #2: (2~{R},3~{R})-2-[(2~{S},3~{R})-3-(hydroxymethyl)-2-(3-methoxy-4-o...

MacromoleculeName: (2~{R},3~{R})-2-[(2~{S},3~{R})-3-(hydroxymethyl)-2-(3-methoxy-4-oxidanyl-phenyl)-7-oxidanyl-2,3-dihydro-1-benzofuran-5-yl]-3,5,7-tris(oxidanyl)-2,3-dihydrochromen-4-one
type: ligand / ID: 2 / Number of copies: 2 / Formula: A1IET
Molecular weightTheoretical: 482.436 Da

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Macromolecule #3: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 3 / Number of copies: 1 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Macromolecule #4: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13...

MacromoleculeName: 2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol
type: ligand / ID: 4 / Number of copies: 2 / Formula: DU0
Molecular weightTheoretical: 516.752 Da
Chemical component information

ChemComp-DU0:
2-[2-[(1~{S},2~{S},4~{S},5'~{R},6~{R},7~{S},8~{R},9~{S},12~{S},13~{R},16~{S})-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icos-18-ene-6,2'-oxane]-16-yl]oxyethyl]propane-1,3-diol

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 8 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 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: 1.0 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 276909
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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