Supercharging the calcium pump: Identification of an activation hotspot on SERCA by cryo-EM.

ABSTRACT: The sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) is a ubiquitous P-type ATPase that restores cytosolic Ca²⁺ to the sarco-endoplasmic reticulum. SERCA is essential for cardiac Ca²⁺ cycling and cellular energy metabolism. Several small molecules enhance SERCA function and show promise in models of metabolic and cardiovascular diseases. However, the structural basis for SERCA activation has remained unknown, hindering mechanism-driven lead optimization. Here we present cryo-EM structures of SERCA bound to two chemically distinct activators: the quinoline derivative CDN1163 (2.6 Å resolution) and a benzofuran derivative UM-52 (3.1 Å resolution). Biochemical assays show that both compounds stimulate Ca²⁺-dependent ATPase activity of SERCA without a

SUBMITTER: Nguyen VH 

PROVIDER: S-EPMC12889739 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature