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Nature 420, 696-700 (12 December 2002) | doi:10.1038/nature01268; Received 15 August 2002; Accepted 29 October 2002; Published online 17 November 2002

Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

Ivan Bosanac1, Jean-René Alattia1, Tapas K. Mal1, Jenny Chan1, Susanna Talarico1, Frances K. Tong1, Kit I. Tong1, Fumio Yoshikawa2, Teiichi Furuichi2, Miwako Iwai3, Takayuki Michikawa3,4, Katsuhiko Mikoshiba2,3,4 & Mitsuhiko Ikura1

  1. Division of Molecular and Structural Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
  2. Laboratory for Developmental Neurobiology and Molecular Neurogenesis, Brain Science Institute, RIKEN, Saitama 351-0198, Japan
  3. Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  4. Calcium Oscillation Project, ICORP, Japan Science and Technology Corporation (JST), Tokyo, 108-0071, Japan

Correspondence to: Mitsuhiko Ikura1 Correspondence and requests for materials should be addressed to M.I. (e-mail: Email: mikura@uhnres.utoronto.ca). The atomic coordinates for InsP3-bound mouse InsP3R1c have been deposited in the Protein Data Bank under accession code 1N4K.

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In a variety of cells, the Ca2+ signalling process is mediated by the endoplasmic-reticulum-membrane-associated Ca2+ release channel, inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R)1. Being ubiquitous and present in organisms ranging from humans to Caenorhabditis elegans, InsP3R has a vital role in the control of cellular and physiological processes as diverse as cell division, cell proliferation, apoptosis, fertilization, development, behaviour, memory and learning2. Mouse type I InsP3R (InsP3R1), found in high abundance in cerebellar Purkinje cells, is a polypeptide with three major functionally distinct regions: the amino-terminal InsP3-binding region, the central modulatory region and the carboxy-terminal channel region2. Here we present a 2.2-Å crystal structure of the InsP3-binding core of mouse InsP3R1 in complex with InsP3. The asymmetric, boomerang-like structure consists of an N-terminal beta-trefoil domain and a C-terminal alpha-helical domain containing an 'armadillo repeat'-like fold. The cleft formed by the two domains exposes a cluster of arginine and lysine residues that coordinate the three phosphoryl groups of InsP3. Putative Ca2+-binding sites are identified in two separate locations within the InsP3-binding core.