Malonate in the nucleotide-binding site traps human AKAP18γδ/d in a novel conformational state

A-kinase anchoring proteins (AKAPs) are a family of proteins that provide spatiotemporal resolution of protein kinase A (PKA) phosphorylation. In the myocardium, PKA and AKAP18 gamma/delta are found in complex with sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca2+ release and re-uptake. For this reason, AKAP18 gamma/delta presents an interesting drug target with therapeutic potential in cardiovascular disease. The crystal structure of the central domain of human AKAP18 gamma has been determined at the atomic resolution of 1.25 angstrom. This first structure of human AKAP18 gamma is trapped in a novel conformation by a malonate molecule bridging the important R-loop with the 2H phosphoesterase motif. Although the physiological substrate of AKAP18 gamma is currently unknown, a potential proton wire deep in the central binding crevice has been indentified, leading to bulk solvent below the R-loop. Malonate complexed with AKAP18 gamma at atomic resolution provides an excellent starting point for structure-guided drug design.