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- PDB-8zko: CryoEM structure of Thyroid Hormone Transporter MCT8 -

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Basic information

Entry
Database: PDB / ID: 8zko
TitleCryoEM structure of Thyroid Hormone Transporter MCT8
ComponentsMonocarboxylate transporter 8
KeywordsMEMBRANE PROTEIN / MCT8 / SLC16A2
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
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3,5,3'TRIIODOTHYRONINE / Monocarboxylate transporter 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsTan, J. / Xiao, Y. / Kong, F. / Zhu, A. / Qian, J. / Yan, C.
Funding support China, 1items
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 17, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Apr 2, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Monocarboxylate transporter 8
B: Monocarboxylate transporter 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,2105
Polymers119,1182
Non-polymers2,0923
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Monocarboxylate transporter 8 / MCT 8 / Monocarboxylate transporter 7 / MCT 7 / Solute carrier family 16 member 2 / X-linked PEST- ...MCT 8 / Monocarboxylate transporter 7 / MCT 7 / Solute carrier family 16 member 2 / X-linked PEST-containing transporter


Mass: 59559.059 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC16A2, MCT7, MCT8, XPCT / Production host: Homo sapiens (human) / References: UniProt: P36021
#2: Chemical ChemComp-T3 / 3,5,3'TRIIODOTHYRONINE / T3 / THYROID HORMONE / LIOTHYRONINE


Mass: 650.973 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H12I3NO4 / Feature type: SUBJECT OF INVESTIGATION / Comment: hormone*YM
#3: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: MCT8 bound with T3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130122 / Symmetry type: POINT
RefinementHighest resolution: 3.13 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036214
ELECTRON MICROSCOPYf_angle_d0.5378407
ELECTRON MICROSCOPYf_dihedral_angle_d5.028909
ELECTRON MICROSCOPYf_chiral_restr0.035942
ELECTRON MICROSCOPYf_plane_restr0.0051024

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