title: A distinct three-helix centipede toxin SSD609 inhibits I(ks) channels by interacting with the KCNE1 auxiliary subunit.
abstract: KCNE1 is a single-span transmembrane auxiliary protein that modulates the voltage-gated potassium channel KCNQ1. The KCNQ1/KCNE1 complex in cardiomyocytes exhibited slow activated potassium (I(ks)) currents. Recently, a novel 47-residue polypeptide toxin SSD609 was purified from Scolopendra subspinipes dehaani venom and showed I(ks) current inhibition. Here, chemically synthesized SSD609 was shown to exert I(ks) inhibition in extracted guinea pig cardiomyocytes and KCNQ1/KCNE1 current attenuation in CHO cells. The K(+) current attenuation of SSD609 showed decent selectivity among different auxiliary subunits. Solution nuclear magnetic resonance analysis of SSD609 revealed a distinctive three-helix conformation that was stabilized by a new disulfide bonding pattern as well as segregated surface charge distribution. Structure-activity studies demonstrated that negatively charged Glu19 in the amphipathic extracellular helix of KCNE1 was the key residue that interacted with SSD609. The distinctive three-helix centipede toxin SSD609 is known to be the first polypeptide toxin acting on channel auxiliary subunit KCNE1, which suggests a new type of pharmacological regulation for ion channels in cardiomyocytes.
authors: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P. R. China.
authors: Peibei
authors: P
authors: Sun
authors: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, P.R. China.
authors: Fangming
authors: F
authors: Wu
authors: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P. R. China.
authors: Ming
authors: M
authors: Wen
authors: Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences &Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan P.R. China.
authors: Xingwang
authors: X
authors: Yang
authors: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P. R. China.
authors: Chenyang
authors: C
authors: Wang
authors: School of Medical Engineering, Hefei University of Technology, Hefei, P. R. China.
authors: Yiming
authors: Y
authors: Li
authors: Department of anesthesiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, P. R. China.
authors: Shufang
authors: S
authors: He
authors: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P. R. China.
authors: Longhua
authors: L
authors: Zhang
authors: Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences &Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan P.R. China.
authors: Yun
authors: Y
authors: Zhang
authors: Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P. R. China.|High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, P.R. China.
authors: Changlin
authors: C
authors: Tian
mesh_terms: D000595:Amino Acid Sequence; D001180:Arthropod Venoms / Q000008:administration & dosage* / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D013329:Structure-Activity Relationship
chemical_list: D001180:Arthropod Venoms; C489622:KCNE1 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits