Addressing the Glycine Rich Loop of Protein Kinases by a Multi Facetted Interaction Network Inhibition of Pka and a Pkb Mimic

Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A PKA and protein kinase B mimic PKAB3 PKA triple mutant . The ligands bind to the hinge region, ribose pocket, and glycine rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine rich loop for gaining high binding potency. X ray co crystal structures revealed a multi facetted network of ligand loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide amp; 960; stacking, and H bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approac

Estrogen And Aging Affect Synaptic Distribution Of Phosphorylated Lim Kinase (Plimk) In Ca1 Region Of Female Rat Hippocampus

17 beta-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young female rats, but not in aged rats. This may be linked to age-related alterations in signaling pathways activated by synaptic estrogen receptor a (ER-a) that potentially regulate spine formation, such as LIM-kinase (LIMK), an actin depolymerizing factor/cofilin kinase. We hypothesized that, as with ER-alpha, phospho-LIM-kinase (pLIMK) may be less abundant or responsive to E in CA1 synapses of aged female rats. To address this, cellular and subcellular distribution of pLIMK-immunoreactivity (IR) in CA1 was analyzed by light and electron microscopy in young and aged female rats that were ovariectomized and treated with either vehicle or E. pLIMK-IR was found primarily in perikarya within the pyramidal cell layer and dendritic shafts and spines in stratum radiatum (SR). While pLIMK-IR was occasionally present in terminals, post-embedding quantitative analysis of SR showed that pLIMK had a predominant post-synaptic localization and was preferentially localized within the postsynaptic density (PSD). The percentage of pLIMK-labeled synapses increased (30%) with E treatment (P<0.02) in young animals, and decreased (43%) with age (P<0.002) regardless of treatment. The pattern of distribution of pLIMK-IR within dendritic spines and synapses was unaffected by age or E treatment, with the exception of an E-induced increase in the non-synaptic core of spines in young females. These data suggest that age-related synaptic alterations similar to those seen with ER-a occur with signaling molecules such as pLIMK, and support the hypothesis that age-related failure of E treatment to increase synapse number in CA1 may be due to changes in the molecular profile of axospinous synapses with respect to signaling pathways linked to formation of additional spines and synapses in response to E. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.Wo

Search for a new weakly interacting particle

A search for events of the type e+e−→ℓ+ℓ−X0, where X0 can be any weakly interacting particle which couples to the Z, has been performed with the ALEPH detector at LEP, by searching for acollinear lepton pairs. Such particles can be excluded up to a mass of 7.0 GeV/c2 for a value of the ratio of branching fractions, Br(Z→X0l+l−)/Br(Z→l+l−), greater than 2.5 × 10−3 if the X0 has third component of isospin, I3 greater than and decays to a pair of virtual gauge bosons. When this analysis is combined with the previous results of the Higgs particle searches from ALEPH, this limit can be extended to an X0 mass of 60 GeV/c2

Production and decay of charmed mesons at the Z resonance

In a sample of 190 000 hadronic Z decays, three signals of charm production are observed: two from the exclusive decays and one in the transverse-momentum distribution of soft hadrons relative to the nearest jet. The features of these signals are in good agreement with expectations based on the standard model and previous measurements of the branching fractions. The number of per hadronic decay of the Z is measured to be (5.11±0.34) × 10−3, and the branching ratio B(D0 → K−π+) is (3.62 ± 0.34 ± 0.44)%. Charm hadronization has been studied. The average fraction of the beam energy carried by the D∗ meson is found to be 〈XE〉c = 0.504−0.017+0.013±0.008, and implications of the measurements on the pseudoscalar-to-vector production ratio of charmed mesons are discussed

Measurement of charge asymmetry in hadronic Z decays

A significant charge asymmetry is observed in the hadronic Z decays with the ALEPH detector at LEP. The asymmetry expressed in terms of the difference in momentum weighted charges in the two event hemispheres is measured to be −= −0.0084±0.0015 (stat.) ±0.0004 (exp. sys.). In the framework of the standard model this can be interpreted as a measurement of the effective electroweak mixing angle, sin2Ow (Mz2=0.2300±0.0034 (stat.) ±0.0010 (exp. sys.) ±0.0038 (theor. sys.) or of the ratio of the vector to axual- vector coupling costants of the electron, gvegAe=+0.073±0.024

Measurement of isolated photon production in hadronic Z decays

The production of high energy isolated photons in hadronic Z decays is measured with the ALEPH detector at LEP using a sample of 180 000 hadronic events. Such photons are mainly radiated by quarks, thus giving direct insights into the early parton showering mechanism. The observed rate is compared with a QCD calculation of final state radiation from quarks

Measurement of the forward - backward asymmetry in Z ---> b anti-b and Z ---> c anti-c

From a sample of 150 000 hadronic Z decays collected with the ALEPH detector at LEP, events containing prompt leptons are used to measure the forward-backward asymmetries for the channels and , giving the results AFBb=0.126±0.028±0.012 and AFBc=0.064±0.039±0.030. These asymmetries correspond to the value of effective electroweak mixing angle at the Z mass sin2θW(mZ2) = 0.2262±0.0053