Crystal Structure of the Calcium ATPase SERCA in Complex to a Novel Anti-Cancer Agent that Targets Multidrug-Resistant Leukemia

Abstract

We have used x-ray crystallography to solve the crystal structure of the sarco/endoplasmic reticulum Ca-ATPase (SERCA) in complex with a novel lead compound (CXL017) that targets multidrug-resistant leukemia (Hermanson et al., Mol Pharmacol 2009). The structure, solved at 3.01A resolution, reveals CXL017 bound to SERCA near the ATP binding site and suggests blockage of the ATP channel as the main mechanism of inhibition. This result confirms that CXL017 binds SERCA at a location that is distinct from the binding sites of other inhibitors of SERCA, and it explains the synergistic relationship that was uncovered between CXL017 and classic SERCA inhibitors (Bleeker et al., Mol. Pharmacol 2013). Further, it provides the platform for structure-guided improvements on this new class of potential anti-cancer agent. This work was funded by a grant from NIH to DDT (R01 GM27906) and a grant from NIH to XC (R01 CA163864).