[English] 日本語
Yorodumi
- EMDB-50629: Human monocarboxylate transporter 8 bound to Silychristin -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-50629
TitleHuman monocarboxylate transporter 8 bound to Silychristin
Map dataMCT8 bound to Silychristin
Sample
  • Complex: Human monocarboxylate transporter 8 bound to Silychristin
    • Protein or peptide: Monocarboxylate transporter 8
    • Protein or peptide: Alfa-tag binding nanobody
  • 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
KeywordsSilychristin / thyroid hormones transport / inhibition / TRANSPORT 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) / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 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 12, 2024-
Header (metadata) releaseMay 21, 2025-
Map releaseMay 21, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBe / Status: Released

-
Structure visualization

Supplemental images

emd_50629.png

Downloads & links

-
Map

FileDownload / File: emd_50629.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMCT8 bound to Silychristin
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: 0.3
Minimum - Maximum-1.1756994 - 2.2516453
Average (Standard dev.)0.0014219923 (±0.03353357)
SymmetrySpace group: 1
Details

EMDB XML:

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

-
Supplemental data

-
Half map: MCT8 bound to Silychristin - half 2

Fileemd_50629_half_map_1.map
AnnotationMCT8 bound to Silychristin - half 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: MCT8 bound to Silychristin - half 1

Fileemd_50629_half_map_2.map
AnnotationMCT8 bound to Silychristin - half 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : Human monocarboxylate transporter 8 bound to Silychristin

EntireName: Human monocarboxylate transporter 8 bound to Silychristin
Components
  • Complex: Human monocarboxylate transporter 8 bound to Silychristin
    • Protein or peptide: Monocarboxylate transporter 8
    • Protein or peptide: Alfa-tag binding nanobody
  • 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

-
Supramolecule #1: Human monocarboxylate transporter 8 bound to Silychristin

SupramoleculeName: Human monocarboxylate transporter 8 bound to Silychristin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71 KDa

-
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

-
Macromolecule #2: Alfa-tag binding nanobody

MacromoleculeName: Alfa-tag binding nanobody / type: protein_or_peptide / ID: 2 / 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

-
Macromolecule #3: (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: 3 / Number of copies: 1 / Formula: A1IET
Molecular weightTheoretical: 482.436 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE

-
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

+
Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101856
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more