title: Relative motions between left flipper and dorsal fin domains favour P2X4 receptor activation.
abstract: Channel gating in response to extracellular ATP is a fundamental process for the physiological functions of P2X receptors. Here we identify coordinated allosteric changes in the left flipper (LF) and dorsal fin (DF) domains that couple ATP-binding to channel gating. Engineered disulphide crosslinking or zinc bridges between the LF and DF domains that constrain their relative motions significantly influence channel gating of P2X4 receptors, confirming the essential role of these allosteric changes. ATP-binding-induced alterations in interdomain hydrophobic interactions among I208, L217, V291 and the aliphatic chain of K193 correlate well with these coordinated relative movements. Mutations on those four residues lead to impaired or fully abolished channel activations of P2X4 receptors. Our data reveal that ATP-binding-induced altered interdomain hydrophobic interactions and the concomitant coordinated motions of LF and DF domains are allosteric events essential for the channel gating of P2X4 receptors.
authors.affiliation: 1] Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2] Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China [3].
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Zhao
authors.affiliation: 1] Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2].
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2] Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China [3].
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Ma
authors.affiliation: Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Li-Dong
authors.initials: LD
authors.lastname: Huang
authors.affiliation: Putuo District Center Hospital, Shanghai University of Chinese Traditional Medicine, Shanghai 200062, China.
authors.forename: Ying-Zhe
authors.initials: YZ
authors.lastname: Fan
authors.affiliation: Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xiao-Yang
authors.initials: XY
authors.lastname: Cheng
authors.affiliation: Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: 1] Institute of Medical Sciences and Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China [2] College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000818:Animals; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D051381:Rats; D058848:Receptors, Purinergic P2X4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D058848:Receptors, Purinergic P2X4; D000255:Adenosine Triphosphate