title: Crystal and EM structures of human phosphoribosyl pyrophosphate synthase I (PRS1) provide novel insights into the disease-associated mutations.
abstract: Human PRS1, which is indispensable for the biosynthesis of nucleotides, deoxynucleotides and their derivatives, is associated directly with multiple human diseases because of single base mutation. However, a molecular understanding of the effect of these mutations is hampered by the lack of understanding of its catalytic mechanism. Here, we reconstruct the 3D EM structure of the PRS1 apo state. Together with the native stain EM structures of AMPNPP, AMPNPP and R5P, ADP and the apo states with distinct conformations, we suggest the hexamer is the enzymatically active form. Based on crystal structures, sequence analysis, mutagenesis, enzyme kinetics assays, and MD simulations, we reveal the conserved substrates binding motifs and make further analysis of all pathogenic mutants.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Xuejuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Peng
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Fuzhou general hospital of Nanjing Command, PLA, Fuzhou 350025, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Niu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Cai
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Maikun
authors.initials: M
authors.lastname: Teng
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, People's Republic of China; Key Laboratory of Structural Biology, Chinese Academy of Sciences, Hefei, Anhui 230026, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D003461:Crystallography; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D012268:Ribose-Phosphate Pyrophosphokinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014965:X-Rays
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase