Morita Maho, Ogawa Haruo, Ohno Osamu, Yamori Takao, Suenaga Kiyotake, Toyoshima Chikashi
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.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
FEBS Lett. 2015 Jun 4;589(13):1406-11. doi: 10.1016/j.febslet.2015.04.056. Epub 2015 May 6.
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.
双列藻素（BLSs）是一种来自海洋蓝藻的大环内酯类化合物，属于细胞毒性天然产物，其靶分子尚不清楚。在此，我们报道BLSs是具有独特结合模式的Ca(2+)泵的高亲和力（Ki约为10 nM）抑制剂。Ca(2+)泵与BLSs复合物的晶体结构在3.2 - 3.5 Å分辨率下显示，BLSs在跨膜区域的细胞质表面附近与泵结合。BLS类似物的晶体结构和活性测量使我们能够确定赋予BLSs作为泵抑制剂高效能的结构特征。
