Structural basis for the transport and substrate selection of human urate transporter 1
Jingjing He,
Guoyun Liu,
Fang Kong,
Qiulong Tan,
Zhenzhou Wang,
Meng Yang,
Yonglin He,
Xiaoxiao Jia,
Chuangye Yan,
Chao Wang,
Hongwu Qian
Affiliations
Jingjing He
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Guoyun Liu
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Fang Kong
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
Qiulong Tan
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China
Zhenzhou Wang
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Meng Yang
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Yonglin He
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Xiaoxiao Jia
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
Chuangye Yan
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
Chao Wang
Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China
Hongwu Qian
Department of Cardiology, First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Corresponding author
Summary: High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30° rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.
