Cyclic adenosine 5'-monophosphate (cAMP) is an ancient signaling molecule, and in vertebrates, a primary target for cAMP is cAMP-dependent protein kinase (PKA). (R(p))-adenosine 3',5'-cyclic monophosphothioate ((R(p))-cAMPS) and its analogues are the only known competitive inhibitors and antagonists for cAMP activation of PKA, while (S(p))-adenosine 3',5'-cyclic monophosphothioate ((S(p))-cAMPS) functions as an agonist. The crystal structures of a Delta(1-91) deletion mutant of the RIalpha regulatory subunit of PKA bound to (R(p))-cAMPS and (S(p))-cAMPS were determined at 2.4 and 2.3 A resolution, respectively. While the structures are similar to each other and to the crystal structure of RIalpha bound to cAMP, differences in the dynamical properties of the protein when (R(p))-cAMPS is bound are apparent. The structures highlight the critical importance of the exocyclic oxygen's interaction with the invariant arginine in the phosphate binding cassette (PBC) and the importance of this interaction for the dynamical properties of the interactions that radiate out from the PBC. The conformations of the phosphate binding cassettes containing two invariant arginine residues (Arg209 on domain A, and Arg333 on domain B) are somewhat different due to the sulfur interacting with this arginine. Furthermore, the B-site ligand together with the entire domain B show significant differences in their overall dynamic properties in the crystal structure of Delta(1-91) RIalpha complexed with (R(p))-cAMPS phosphothioate analogue ((R(p))-RIalpha) compared to the cAMP- and (S(p))-cAMPS-bound type I and II regulatory subunits, based on the temperature factors. In all structures, two structural solvent molecules exist within the A-site ligand binding pocket; both mediate water-bridged interactions between the ligand and the protein. No structured waters are in the B-site pocket. Owing to the higher resolution data, the N-terminal segment (109-117) of the RIalpha subunit can also be traced. This strand forms an intermolecular antiparallel beta-sheet with the same strand in an adjacent molecule and implies that the RIalpha subunit can form a weak homodimer even in the absence of its dimerization domain.
The first deep geothermal exploration borehole (995 m) to be drilled in the UK for over 20 years was completed at Eastgate (Weardale, Co. Durham) in December 2004. It penetrated 4 m of sandy till (Quaternary), 267.5 m of Lower Carboniferous strata (including the Whin Sill), and 723.5 m of the Weardale Granite (Devonian), with vein mineralization occurring to 913 m. Unlike previous geothermal investigations of UK radiothermal granites that focused on the hot dry rock concept, the Eastgate Borehole was designed to intercept deep fracture-hosted brines associated with the major, geologically ancient, hydrothermal vein systems. Abundant brine (≤46 °C) was encountered within natural fracture networks of very high permeability (transmissivity
c
. 2000 darcy m) within granite. Evidence for the thermal history of the Carboniferous rocks from phytoclast reflectance measurements shows very high values (≥3.3%) indicating maximum temperatures of 130 °C prior to intrusion of the Whin Sill. Geochemical analysis of cuttings samples from the Eastgate Borehole suggests radiothermal heat production rates for unaltered Weardale Granite averaging 4.1 μW m
−3
, with a mean geothermal gradient of 38 °C km
−1
. The Eastgate Borehole has significant exploitation potential for direct heat uses; it demonstrates the potential for seeking hydrothermal vein systems within radiothermal granites as targets for geothermal resources.
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