9DWY

Cryo-EM structure of human MCT8 in complex with thyroid hormone T3

Summary for 9DWY

• Entry DOI: 10.2210/pdb9dwy/pdb
• EMDB information: 47274
• Descriptor: Monocarboxylate transporter 8, 3,5,3'TRIIODOTHYRONINE (2 entities in total)
• Functional Keywords: slc transporter, thyroid hormone, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 63980.20

Authors

Ge, Y.,Dou, T.,Jiang, J.,Huang, P. (deposition date: 2024-10-10, release date: 2025-07-16, Last modification date: 2025-07-30)

Primary citation

Ge, Y.,Dou, T.,Nguyen, T.U.,Yadav, G.P.,Wensel, T.G.,Jiang, J.,Huang, P.
Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1.
Cell, 2025

PubMed Abstract: Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones across the blood-brain barrier and into the central nervous system. Mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), an X-linked birth defect characterized by neurodevelopmental impairments and peripheral hyperthyroidism, whereas OATP1C1 deficiency is linked to brain hypometabolism and progressive neurodegeneration. Here, we report cryoelectron microscopy (cryo-EM) structures of MCT8 and OATP1C1 bound with the active thyroid hormone triiodothyronine (T3) and the prohormone thyroxine (T4) at 2.9 and 2.3 Å resolutions, respectively. Combined with functional studies, we elucidate their distinct thyroid hormone recognition and transport mechanisms and explain disease mutations. Although extracellular allosteric sites are not a common feature of SLC transporters, we identify one in OATP1C1. Collectively, these findings illuminate key aspects of thyroid hormone transport, a fundamental process in development and disease.

PubMed: 40680733
DOI: 10.1016/j.cell.2025.06.032

Experimental method

ELECTRON MICROSCOPY (2.9 Å)