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941.
Amar S. Prashad Daniel Wang Joan Subrath Biqi Wu Melissa Lin Mei-Yi Zhang Natasha Kagan Julie Lee Xiaoke Yang Agnes Brennan Divya Chaudhary Xin Xu Louis Leung Jack Wang Diane H. Boschelli 《Bioorganic & medicinal chemistry letters》2009,19(19):5799-5802
We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCθ (IC50 = 4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCθ. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCθ. 相似文献
942.
Louis G. Zachos 《Journal of theoretical biology》2009,259(3):646-125
A new computational model has been developed to simulate growth of regular sea urchin skeletons. The model incorporates the processes of plate addition and individual plate growth into a composite model of whole-body (somatic) growth. A simple developmental model based on hypothetical morphogens underlies the assumptions used to define the simulated growth processes. The data model is based on a Delaunay triangulation of plate growth center points, using the dual Voronoi polygons to define plate topologies. A spherical frame of reference is used for growth calculations, with affine deformation of the sphere (based on a Young-Laplace membrane model) to result in an urchin-like three-dimensional form. The model verifies that the patterns of coronal plates in general meet the criteria of Voronoi polygonalization, that a morphogen/threshold inhibition model for plate addition results in the alternating plate addition pattern characteristic of sea urchins, and that application of the Bertalanffy growth model to individual plates results in simulated somatic growth that approximates that seen in living urchins. The model suggests avenues of research that could explain some of the distinctions between modern sea urchins and the much more disparate groups of forms that characterized the Paleozoic Era. 相似文献
943.
Cooperia oncophora is an important parasitic nematode of cattle with a wide distribution in temperate areas. Twenty Holstein nematode-naïve bull calves were experimentally infected with approximately 100,000 infective L3s and infection was allowed to progress for 7, 14, 28, 42 days, respectively. This experiment was conducted to identify putative recognition and inflammatory pathways in the host-parasite relationship. Gene expression profiles of the small intestine were compared using a high-density bovine 60 mer oligo microarray. A total of 310 genes were differentially expressed during the course of infection. The pathways and regulatory networks significantly impacted by the infection were analysed. A total of 22 canonical pathways and nine regulatory networks were significantly affected during infection. During the early phase of the infection (7 days p.i.), parasites suppressed the acute phase response and the complement system of the host. At 14 days p.i., three out of the six pathways impacted were related with retinoid X receptor (RXR) functions. At 28 days p.i., the effects on RXR were less evident. The host response shifted to lipid metabolism and signalling, especially eicosanoid production and signalling, suggesting that eicosanoid-mediated inflammation might be a major host defence mechanism. By 42 days p.i., the pathways impacted involved glycosphingolipid biosynthesis and transforming growth factor β (TGFβ signalling. The expression of cadherin-like 26 (CDH26) was strongly up-regulated starting at 14 days p.i. and peaked at 28 days p.i. The extent of its expression is positively correlated with the infiltration of eosinophils (R = 0.82) and coincides with the number of adult parasites in the tissue. CDH26 demonstrated an expression profile similar to two other cell adhesion molecules involved in recognition of carbohydrates on foreign organisms, collectin and galectin, suggesting that it may serve as a pattern recognition molecule for C. oncophora. These results provide a potential molecular roadmap for future studies aimed at defining host immune responses and understanding protective immunity against gastrointestinal nematodes. 相似文献
944.
945.
Luciane Mendes Hatadani James O. McInerney Hermes Fonseca de Medeiros Ana Carolina Martins Junqueira Ana Maria de Azeredo-Espin Louis Bernard Klaczko 《Molecular phylogenetics and evolution》2009,51(3):595-600
We suggest a new phylogenetic hypothesis for the tripunctata radiation based on sequences of mitochondrial genes. Phylogenetic trees were reconstructed by parsimony, maximum likelihood and Bayesian methods. We performed tests for hypotheses of monophyly for taxonomic groups and other specific hypotheses. Results reject the monophyly for the tripunctata group whereas monophyly is not rejected for the tripunctata radiation and other specific groups within the radiation. Although most of the basal nodes were unresolved we were able to identify four clusters within the tripunctata radiation. These results suggest the collection of additional data before a proper taxonomic revision could be proposed. 相似文献
946.
Dani?l B. van Schalkwijk Albert A. de Graaf Ben van Ommen Kees van Bochove Patrick C. N. Rensen Louis M. Havekes Niek C. A. van de Pas Huub C. J. Hoefsloot Jan van der Greef Andreas P. Freidig 《Journal of lipid research》2009,50(12):2398-2411
Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given. 相似文献
947.
Robert M. Immormino Louis E. Metzger IV D. Eric Dollins Brian S.J. Blagg 《Journal of molecular biology》2009,388(5):1033-238
Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Despite the myriad of inhibitors, none to date have been designed to bind specifically to just one of the four mammalian Hsp90 paralogs, which are cytoplasmic Hsp90α and β, endoplasmic reticulum GRP94, and mitochondrial Trap-1. Given that each of the Hsp90 paralogs is responsible for chaperoning a distinct set of client proteins, specific targeting of one Hsp90 paralog may result in higher efficacy and therapeutic control. Specific inhibitors may also help elucidate the biochemical roles of each Hsp90 paralog. Here, we present side-by-side comparisons of the structures of yeast Hsp90 and mammalian GRP94, bound to the pan-Hsp90 inhibitors geldanamycin (Gdm) and radamide. These structures reveal paralog-specific differences in the Hsp90 and GRP94 conformations in response to Gdm binding. We also report significant variation in the pose and disparate binding affinities for the Gdm-radicicol chimera radamide when bound to the two paralogs, which may be exploited in the design of paralog-specific inhibitors. 相似文献
948.
The kinetics of myosin regulatory light chain (MLC) phosphorylation by recombinant AMP-activated protein kinase (AMPK) were compared with commercial AMPK from rat liver and smooth muscle myosin light chain kinase (smMLCK). With identical amounts of activity units, initial rates of phosphorylation of MLC were at least 100-fold less with recombinant AMPK compared to smMLCK, whereas with rat liver AMPK significant phosphorylation was seen. In Madin-Darby Canine Kidney cells, AMPK activation led to an increase in MLC phosphorylation, which was decreased by a Rho kinase inhibitor without affecting AMPK activation. Therefore, MLC phosphorylation during energy deprivation does not result from direct phosphorylation by AMPK.
Structured summary
- MINT-6800264: smMLCK (uniprotkb:P11799) phosphorylates (MI:0217) MLC (uniprotkb:P08590) by protein kinase assay (MI:0424)
- MINT-6800252: AMPK (uniprotkb:Q13131) phosphorylates (MI:0217) ACC2 (uniprotkb:000763) by protein kinase assay (MI:0424)
949.
950.
Vinodh B. Kurella Jessica M. Richard Courtney L. Parke Louis F. LeCour Jr. Henry D. Bellamy David K. Worthylake 《The Journal of biological chemistry》2009,284(22):14857-14865
IQGAP1 is a 190-kDa molecular scaffold containing several domains required
for interaction with numerous proteins. One domain is homologous to Ras
GTPase-activating protein (GAP) domains. However, instead of accelerating
hydrolysis of bound GTP on Ras IQGAP1, using its GAP-related domain (GRD)
binds to Cdc42 and Rac1 and stabilizes their GTP-bound states. We report here
the crystal structure of the isolated IQGAP1 GRD. Despite low sequence
conservation, the overall structure of the GRD is very similar to the GAP
domains from p120 RasGAP, neurofibromin, and SynGAP. However, instead of the
catalytic “arginine finger” seen in functional Ras GAPs, the GRD
has a conserved threonine residue. GRD residues 1099–1129 have no
structural equivalent in RasGAP and are seen to form an extension at one end
of the molecule. Because the sequence of these residues is highly conserved,
this region likely confers a functionality particular to IQGAP family GRDs. We
have used isothermal titration calorimetry to demonstrate that the isolated
GRD binds to active Cdc42. Assuming a mode of interaction similar to that
displayed in the Ras-RasGAP complex, we created an energy-minimized model of
Cdc42·GTP bound to the GRD. Residues of the GRD that contact Cdc42 map
to the surface of the GRD that displays the highest level of sequence
conservation. The model indicates that steric clash between threonine 1046
with the phosphate-binding loop and other subtle changes would likely disrupt
the proper geometry required for GTP hydrolysis.The small GTPase Ras functions as a binary switch in cell signaling
processes. When bound to GTP, Ras is able to interact with effector proteins,
including Raf kinase, and alter their activities. Ras signaling is terminated
when bound GTP is hydrolyzed to GDP and inorganic phosphate. The basal rate of
GTP hydrolysis on Ras is quite slow (∼1.2 × 10–4
s–1), but this rate of hydrolysis can be enhanced
∼105-fold by interaction with a GTPase-activating protein
(GAP)2
(1). Several RasGAPs have been
identified to date including p120 RasGAP and neurofibromin (NF1). The Rho
family of Ras-related small GTPases also function as binary switches in cell
signaling processes. Whereas the intrinsic rate of GTP hydrolysis on Rho
proteins is faster than Ras, this rate can also be stimulated by interaction
with a RhoGAP. Examination of the structures of the GAP domains of p120RasGAP
(2), neurofibromin
(3), SynGAP
(4), and the GAP domains from
the RhoGAPs p50 RhoGAP and the Bcr homology domain of phosphatidylinositol
3-kinase (5,
6) indicates that although
ostensibly different, these all-helical domains are structurally related
(7).IQGAP1 was discovered by chance during an attempt to isolate novel matrix
metalloproteinases (8).
Analysis reveals that the protein contains several discrete domains and motifs
including a region containing four isoleucine- and glutamine-rich motifs (IQ
repeats) and a region with sequence homology to the Ras-specific GAP domains
of p120RasGAP, NF1, and SynGAP
(2–4,
8). Subsequently, two homologs,
IQGAP2 and IQGAP3, have been discovered. The IQ repeats have been shown to
mediate binding to calmodulin and calmodulin-like proteins (e.g.
S100, myosin essential light chain), whereas the GAP-related domain (GRD) does
not appear to bind to Ras but instead is necessary for binding to the Rho
family GTPases Cdc42 and Rac1, primarily in their active forms
(9–11).
However, instead of accelerating hydrolysis of GTP, IQGAP1 preserves the
activated states of Cdc42 and Rac1 to the extent that overexpression of IQGAP1
in cells increases the levels of active GTPase
(12). Because IQGAP1
expression increases the level of activated Cdc42, initially there was some
confusion as to whether the protein might not represent a novel guanine
nucleotide exchange factor. However it now appears that IQGAP1 is an effector
of Cdc42 and Rac1 and preserves their activated states by tightly binding to
the GTPases and stabilizing them in a conformation not conducive to GTP
hydrolysis. IQGAP1 appears to be such an important effector for Cdc42 that
abrogation of binding to IQGAP1 not only reduces the levels of active Cdc42,
it also reduces membrane-localized Cdc42 and the cellular response to
bradykinin (12).A growing body of evidence implicates IQGAP1 in carcinogenesis. Expression
of IQGAP1 increases during the transition from a minimally to a highly
metastastic form of melanoma, and IQGAP1 has been found to be overexpressed in
ovarian, breast, lung, and colorectal cancers
(13–17).
In vitro, overexpressed IQGAP1 enhances cell motility and
invasiveness in a process that requires Cdc42 and Rac
(18). β-Catenin is one of
the many binding partners of IQGAP1 identified to date. IQGAP1 has been shown
to bind to β-catenin and interfere with β-catenin binding to
α-catenin, an interaction necessary for stable cell-cell adhesion
(19). Another study found that
IQGAP2 knock-out mice overexpress IQGAP1 and developage-dependent liver cancer
and apoptosis (20).To better understand how a protein domain homologous to others that
accelerate GTP hydrolysis can function as an effector and preserve the
GTP-bound state, we have determined the x-ray structure of the IQGAP1 GRD.
Despite low sequence identity, the GRD structure is quite similar to the GAP
domains of p120, neurofibromin, and SynGAP; however, unlike those domains, the
GRD possesses a conserved threonine in place of the catalytic arginine finger
and has a 31-residue insertion that projects from one end of the molecule.
Using the coordinates of Ras·GDP·AlF3 in complex with
the GAP domain of p120, we built a model of Cdc42·GTP bound to the GRD.
The model indicates that a steric clash between the conserved
Thr1046 and the phosphate-binding loop of Cdc42 and other subtle
changes within the active site would likely preclude nucleotide hydrolysis.
Sequence conservation mapped to the surface of the GRD indicates that the
surface with the highest degree of conservation overlaps with the surface that
makes contacts to Cdc42 in the model. 相似文献