Malonate in the nucleotide‐binding site traps human AKAP18γ/δ in a novel conformational state. Issue 8 (4th August 2016)

• Record Type: Journal Article
• Authors: Bjerregaard-Andersen, Kaare; Østensen, Ellen; Scott, John D.; Taskén, Kjetil; Morth, Jens Preben
• Is Part Of: Acta crystallographica. Volume 72:Issue 8(2016:Aug.)
• Page Start: 591
• Page End: 597
• Publication Date: 2016-08-04
• Subjects: A‐kinase anchoring protein -- AKAP7 -- PKA -- phospholamban -- signalling -- AKAP -- drug design -- PKA -- proton wire; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X16010189
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : AKAP18γ/δ is recognized for its involvement in modulating cardiac Ca 2+ release and re‐uptake and is a potential drug target in cardiovascular disease. The atomic resolution crystal structure of the central domain of AKAP18γ/δ complexed with malonate presents an optimal template for structure‐guided drug design. Abstract : 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 AKAP18γ/δ are found in complex with sarcoendoplasmic reticulum Ca 2+ ‐ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca 2+ release and re‐uptake. For this reason, AKAP18γ/δ presents an interesting drug target with therapeutic potential in cardiovascular disease. The crystal structure of the central domain of human AKAP18γ has been determined at the atomic resolution of 1.25 Å. This first structure of human AKAP18γ 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 AKAP18γ 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 AKAP18γ at atomic resolution provides an excellent starting point for structure‐guided drug design.