Malonate in the nucleotide-binding site traps human AKAP18 γ / δ 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 γ / δ 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 γ / δ presents an interesting drug target with therapeutic potential in cardiovascular disease. The crystal structure of the central domain of human AKAP18 γ has been determined at the atomic resolution of 1.25   Å . This first structure of human AKAP18 γ 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 γ 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 γ at atomic resolution provides an excellent starting point for structure-guided drug design.
Source: Acta Crystallographica Section F - Category: Biochemistry Authors: Tags: A-kinase anchoring protein AKAP7 PKA phospholamban signalling drug design proton wire research communications Source Type: research