Tan Jiaxin, Xiao Yuan, Kong Fang, Qian Jiawei, Zhu Angqi, Yan Chuangye
Beijing Frontier Research Center for Biological Structure, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
Nat Commun. 2025 Mar 26;16(1):2958. doi: 10.1038/s41467-025-58131-8.
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.
甲状腺激素（THs），包括T4（3,5,3',5'-四碘-L-甲状腺原氨酸）和T3（3,5,3'-三碘-L-甲状腺原氨酸），在调节组织发育和基础代谢中发挥着关键作用。单羧酸转运蛋白8（MCT8）是TH转运中的关键参与者，以其对THs的高特异性和亲和力以及与致病性突变引起的艾伦-赫登-达德利综合征（AHDS）的直接关联而闻名。在本研究中，我们展示了与底物T3或抑制剂水飞蓟宾结合的人MCT8的冷冻电镜结构，二者均处于向外开放构象，分辨率为3.0 - 3.2 Å。MCT8形成同型二聚体，脂质分子位于二聚化界面。T3的羧基由Arg371识别，而其三个碘原子与不同的疏水腔相互作用。水飞蓟宾也由Arg371识别，与T3竞争结合。通过结构导向的生化分析补充，我们的研究阐明了底物识别和转运机制以及抑制剂水飞蓟宾的作用模式。这些发现可能为开发针对TH相关疾病的靶向治疗提供见解。
