Structural insights into thyroid hormone transporter MCT8
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 transporter 8 (MCT8) is a key player in TH transport, known for its high specificity and aff...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58131-8 |
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| author | Jiaxin Tan Yuan Xiao Fang Kong Jiawei Qian Angqi Zhu Chuangye Yan |
| author_facet | Jiaxin Tan Yuan Xiao Fang Kong Jiawei Qian Angqi Zhu Chuangye Yan |
| author_sort | Jiaxin Tan |
| collection | DOAJ |
| description | 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 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. |
| format | Article |
| id | doaj-art-48ca5d2619b74095ad0bb5ef12cc80e6 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-48ca5d2619b74095ad0bb5ef12cc80e62025-08-20T02:49:33ZengNature PortfolioNature Communications2041-17232025-03-011611910.1038/s41467-025-58131-8Structural insights into thyroid hormone transporter MCT8Jiaxin Tan0Yuan Xiao1Fang Kong2Jiawei Qian3Angqi Zhu4Chuangye Yan5Beijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58131-8 |
| spellingShingle | Jiaxin Tan Yuan Xiao Fang Kong Jiawei Qian Angqi Zhu Chuangye Yan Structural insights into thyroid hormone transporter MCT8 Nature Communications |
| title | Structural insights into thyroid hormone transporter MCT8 |
| title_full | Structural insights into thyroid hormone transporter MCT8 |
| title_fullStr | Structural insights into thyroid hormone transporter MCT8 |
| title_full_unstemmed | Structural insights into thyroid hormone transporter MCT8 |
| title_short | Structural insights into thyroid hormone transporter MCT8 |
| title_sort | structural insights into thyroid hormone transporter mct8 |
| url | https://doi.org/10.1038/s41467-025-58131-8 |
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