Biselyngbyasides, cytotoxic marine macrolides, are novel and potent inhibitors of the Ca(2+) pumps with a unique mode of binding

FEBS Lett. 2015 Jun 4;589(13):1406-11. doi: 10.1016/j.febslet.2015.04.056. Epub 2015 May 6.

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.

Keywords: Ca(2+)-ATPase; Crystal structure; High affinity; Inhibitor; Ion pump; Macrolide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Cyanobacteria / chemistry
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Kinetics
  • Macrolides / chemistry
  • Macrolides / metabolism
  • Macrolides / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Marine Toxins / chemistry
  • Marine Toxins / metabolism
  • Marine Toxins / pharmacology*
  • Molecular Structure
  • Protein Binding
  • Protein Structure, Tertiary
  • Rabbits
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / chemistry
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Seawater / microbiology

Substances

  • Enzyme Inhibitors
  • Macrolides
  • Marine Toxins
  • biselyngbyaside
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases