人源硫酸盐转运蛋白DTDST的结构生物学研究

人源硫酸盐转运蛋白DTDST的结构生物学研究

池希敏，李晓荣，黄邦栋，周  强^*

（1.西湖大学生命科学学院，西湖实验室（生命科学和生物医学浙江省实验室），浙江省结构生物学研究重点实验室，浙江杭州310024；2.浙江西湖高等研究院，生物学研究所，浙江杭州310024）

摘   要  软骨畸形发育不良（diastrophic dysplasia）是一种严重的常染色体隐性遗传疾病，由畸形发育不良硫酸盐转运蛋白（diastrophic dysplasia sulfate transporter，DTDST）的突变引起，目前没有有效的治疗手段。DTDST也称为SLC26A2，属于人源溶质转运蛋白SLC26家族。由于缺乏必要的结构信息，针对DTDST的药物研发进展缓慢。本研究解析了人源硫酸盐转运蛋白DTDST的冷冻电镜三维结构，揭示了其二聚化作用界面和底物结合口袋的结构特征，并比较了DTDST和已报道的其他同源蛋白的构象。该研究结果加深了对SLC26家族蛋白底物识别和转运机制的了解，为治疗软骨畸形发育不良的药物开发提供了结构基础。

关键词   硫酸盐转运蛋白；SLC26A2；软骨畸形发育不良；冷冻电镜结构

中图分类号：Q518.2；Q591.7；R682；R596 文献标识码：A     doi:10.3969/j.issn.1000-6281.2023.01.004

Structural insights of human sulfate transporter DTDST

CHI Xi-min ，LI Xiao-rong ，HUANG Bang-dong ，ZHOU Qiang ^*

(1.Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University，Hangzhou Zhejiang 310024；2. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou Zhejiang 310024，China)

Abstract   Diastrophic dysplasia is a severe autosomal recessive hereditary disease mainly caused by mutations in diastrophic dysplasia sulfate transporter (DTDST) encoded by SLC26A2 gene, for which no effective therapeutic methods are available at present. The respective drug development is postponed due to the lack of structural information. Here, we report the cryo-EM structure of human sulfate transport protein DTDST, and reveal its structure characteristics, such as dimerization and substrate binding. This work enhances the understanding of substrate recognition and transport mechanism of DTDST, providing structural basis for development of therapeutic methods for dystrophic dysplasia.

Keywords   diastrophic dysplasia sulfate transporter；SLC26A2；Diastrophic dysplasia；Cryo-EM structure

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