title: Biselyngbyasides, cytotoxic marine macrolides, are novel and potent inhibitors of the Ca(2+) pumps with a unique mode of binding.
abstract: Biselyngbyasides (BLSs), macrolides from a marine cyanobacterium, are cytotoxic natural products whose target molecule is unknown. Here we report that BLSs are high affinity (Ki∼10 nM) inhibitors of Ca(2+)-pumps with a unique binding mode. The crystal structures of the Ca(2+)-pump in complex with BLSs at 3.2-3.5 Å-resolution show that BLSs bind to the pump near the cytoplasmic surface of the transmembrane region. The crystal structures and activity measurement of BLS analogs allow us to identify the structural features that confer high potency to BLSs as inhibitors of the pump.
authors.affiliation: Department of Chemistry, Keio University, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Morita
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Chemistry, Keio University, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohno
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: Department of Chemistry, Keio University, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Suenaga
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: ct@iam.u-tokyo.ac.jp.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Toyoshima
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008387:Marine Toxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012623:Seawater / Q000382:microbiology
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D008387:Marine Toxins; C541338:biselyngbyaside; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Ca(2+)-ATPase; Crystal structure; High affinity; Inhibitor; Ion pump; Macrolide