title: Malonate in the nucleotide-binding site traps human AKAP18γ/δ in a novel conformational state.
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.
authors.affiliation: Centre for Molecular Medicine Norway, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
authors.forename: Kaare
authors.initials: K
authors.lastname: Bjerregaard-Andersen
authors.affiliation: Biotechnology Centre, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Østensen
authors.affiliation: Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, PO Box 357370, Seattle, WA 98195, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.affiliation: Centre for Molecular Medicine Norway, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.affiliation: Centre for Molecular Medicine Norway, University of Oslo, PO Box 1137, N-0318 Oslo, Norway.
authors.forename: Jens Preben
authors.initials: JP
authors.lastname: Morth
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008314:Malonates / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010957:Plasmids / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D054758:A Kinase Anchor Proteins; C112596:AKAP7 protein, human; D008314:Malonates; D008565:Membrane Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C030290:malonic acid; D010450:Endopeptidases; C099488:TEV protease
keywords: A-kinase anchoring protein; AKAP; AKAP7; PKA; drug design; phospholamban; proton wire; signalling