12 research outputs found
Deciphering the Arginine-Binding Preferences at the Substrate-Binding Groove of Ser/Thr Kinases by Computational Surface Mapping
Protein kinases are key signaling enzymes that catalyze the transfer of γ-phosphate from an ATP molecule to a phospho-accepting residue in the substrate. Unraveling the molecular features that govern the preference of kinases for particular residues flanking the phosphoacceptor is important for understanding kinase specificities toward their substrates and for designing substrate-like peptidic inhibitors. We applied ANCHORSmap, a new fragment-based computational approach for mapping amino acid side chains on protein surfaces, to predict and characterize the preference of kinases toward Arginine binding. We focus on positions P−2 and P−5, commonly occupied by Arginine (Arg) in substrates of basophilic Ser/Thr kinases. The method accurately identified all the P−2/P−5 Arg binding sites previously determined by X-ray crystallography and produced Arg preferences that corresponded to those experimentally found by peptide arrays. The predicted Arg-binding positions and their associated pockets were analyzed in terms of shape, physicochemical properties, amino acid composition, and in-silico mutagenesis, providing structural rationalization for previously unexplained trends in kinase preferences toward Arg moieties. This methodology sheds light on several kinases that were described in the literature as having non-trivial preferences for Arg, and provides some surprising departures from the prevailing views regarding residues that determine kinase specificity toward Arg. In particular, we found that the preference for a P−5 Arg is not necessarily governed by the 170/230 acidic pair, as was previously assumed, but by several different pairs of acidic residues, selected from positions 133, 169, and 230 (PKA numbering). The acidic residue at position 230 serves as a pivotal element in recognizing Arg from both the P−2 and P−5 positions
Seismotectonics of the Cyprian Arc
The Cyprian Arc forms the plate boundary between the Anatolian plate in the north and the Nubian and Sinai plates in the south. We examine the tectonic setting and seismic activity along the arc in light of new geodetic studies indicating relative NE–SW plate motions across the arc. The first-order tectonic variations are determined by the arc's geometry. The eastern arc, oriented subparallel to relative motion, is dominated by transcurrent tectonism. The western arc is oriented almost normal to relative plate motion and is subjected to convergent processes. Variations in the level and depth of seismic activity along the western arc suggest that the northwestern section of the arc represents a subduction boundary, whereas the southeastern section represents a collision boundary. The two tectonic domains of the western arc are separated by a NE–SW trending tear fault, which produces large earthquakes, such as the MW = 6.8, 1996 Paphos earthquake. We compare the geometrically similar Cyprian and Hellenic Arcs and find significant differences in the rate, direction and type of convergence across the two arcs. The Hellenic Arc is subjected mainly to subduction, whereas the shorter Cyprian Arc is subjected to subduction, collision and transcurrent tectonic processes
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