Bjerregaard-Andersen Kaare, Østensen Ellen, Scott John D, Taskén Kjetil, Morth Jens Preben
Centre for Molecular Medicine Norway, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
Biotechnology Centre, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
Acta Crystallogr F Struct Biol Commun. 2016 Aug;72(Pt 8):591-7. doi: 10.1107/S2053230X16010189. Epub 2016 Jul 13.
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.
A激酶锚定蛋白（AKAPs）是一类能对蛋白激酶A（PKA）磷酸化作用提供时空分辨率的蛋白质。在心肌中，PKA和AKAP18γ/δ与肌浆网Ca(2+) -ATP酶2（SERCA2）和受磷蛋白（PLB）形成复合物。这种大分子复合物提供了一种方式，通过它锚定的PKA可以动态调节细胞质Ca(2+) 的释放和再摄取。因此，AKAP18γ/δ是一个在心血管疾病中具有治疗潜力的有趣药物靶点。人AKAP18γ中心结构域的晶体结构已在1.25 Å的原子分辨率下确定。人AKAP18γ的这一首个结构被一个丙二酸分子捕获在一种新构象中，该丙二酸分子将重要的R环与2H磷酸酯酶基序连接起来。尽管目前尚不清楚AKAP18γ的生理底物，但已在中心结合裂隙深处确定了一条潜在的质子线，通向R环下方的大量溶剂。以原子分辨率与AKAP18γ复合的丙二酸为结构导向的药物设计提供了一个绝佳的起点。
