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61.
62.
Spacing of the -10 and -35 regions in the tac promoter. Effect on its in vivo activity 总被引:17,自引:0,他引:17
In the tac promoter (deBoer, H. A., Comstock, L. J., and Vasser, M. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 21-25) the spacing between the -35 and -10 consensus sequences is 16 base pairs. Between these two regions we inserted 1 or 2 base pairs to increase the distance to 17 base pairs (trc promoter) or 18 base pairs (tic promoter). The activities of the three promoters were compared in vivo by fusion to the chloramphenicol acetyltransferase or to the Escherichia coli 4.5 S RNA gene. Both measurements gave consistent results. The trc and tic promoters are on average about 90% and 65% as active as the tac promoter, respectively. 相似文献
63.
H F Noller J Kop V Wheaton J Brosius R R Gutell A M Kopylov F Dohme W Herr D A Stahl R Gupta C R Waese 《Nucleic acids research》1981,9(22):6167-6189
A secondary structure model for 23S ribosomal RNA has been constructed on the basis of comparative sequence data, including the complete sequences from E. coli. Bacillus stearothermophilis, human and mouse mitochondria and several partial sequences. The model has been tested extensively with single strand-specific chemical and enzymatic probes. Long range base-paired interactions organize the molecule into six major structural domains containing over 100 individual helices in all. Regions containing the sites of interaction with several ribosomal proteins and 5S RNA have been located. Segments of the 23S RNA structure corresponding to eucaryotic 5.8S and 25 RNA have been identified, and base paired interactions in the model suggest how they are attached to 28S RNA. Functionally important regions, including possible sites of contact with 30S ribosomal subunits, the peptidyl transferase center and locations of intervening sequences in various organisms are discussed. Models for molecular 'switching' of RNA molecules based on coaxial stacking of helices are presented, including a scheme for tRNA-23S RNA interaction. 相似文献
64.
65.
Seungil Han Anil Mistry Jeanne S. Chang David Cunningham Matt Griffor Peter C. Bonnette Hong Wang Boris A. Chrunyk Gary E. Aspnes Daniel P. Walker Arthur D. Brosius Leonard Buckbinder 《The Journal of biological chemistry》2009,284(19):13193-13201
Proline-rich tyrosine kinase 2 (PYK2) is a cytoplasmic, non-receptor
tyrosine kinase implicated in multiple signaling pathways. It is a negative
regulator of osteogenesis and considered a viable drug target for osteoporosis
treatment. The high-resolution structures of the human PYK2 kinase domain with
different inhibitor complexes establish the conventional bilobal kinase
architecture and show the conformational variability of the DFG loop. The
basis for the lack of selectivity for the classical kinase inhibitor,
PF-431396, within the FAK family is explained by our structural analyses.
Importantly, the novel DFG-out conformation with two diarylurea inhibitors
(BIRB796, PF-4618433) reveals a distinct subclass of non-receptor tyrosine
kinases identifiable by the gatekeeper Met-502 and the unique hinge loop
conformation of Leu-504. This is the first example of a leucine residue in the
hinge loop that blocks the ATP binding site in the DFG-out conformation. Our
structural, biophysical, and pharmacological studies suggest that the unique
features of the DFG motif, including Leu-504 hinge-loop variability, can be
exploited for the development of selective protein kinase inhibitors.Proline-rich tyrosine kinase 2
(PYK2)2 and focal
adhesion kinase (FAK) comprise the focal adhesion kinase subfamily of
non-receptor tyrosine kinases. PYK2 and FAK are large multidomain proteins
containing an N-terminal FERM domain, a central catalytic domain, and a
C-terminal segment containing dual proline rich (PR) subdomains and a focal
adhesion targeting (FAT) region
(1,
2). While FAK is widely
expressed, PYK2 expression is relatively restricted with highest levels in
brain and the hematopoeitic system. Unlike FAK, optimal PYK2 activation is
dependent on Ca2+ mobilization. PYK2 (-/-) animals have been
described previously, and develop normally
(3,
4). Characterization of the
immune system of PYK2(-/-) animals revealed the absence of marginal zone
B-cells along with abnormal T-cell independent type II responses
(4), and altered macrophage
morphology, migration and signaling in response to cell attachment or
chemokine treatment (3). These
studies strengthen the link between PYK2 and signaling through chemokine and
integrin receptors. In addition, PYK2(-/-) mice were shown to have increased
susceptibility to diet-induced obesity and diabetes
(5).Recently, the characterization of PYK2(-/-) mice showed a high bone mass
phenotype resulting from increased osteogenesis and osteoblast activity. Using
PYK2(-/-) mouse bone marrow cultures and hMSCs expressing a PYK2 shRNA,
elimination or reduction of PYK2 protein levels resulted in significantly
enhanced osteogeogenesis. Importantly, the daily administration of a
pyrimidine-based PYK2 inhibitor, PF-431396, increased bone formation, and
protected against bone loss in ovariectomized rats
(6). PYK2(-/-) mice showed mild
osteopetrosis which was attributed to the impairment in osteoclast function
(7). Therefore, the high bone
mass phenotype may result from both enhanced osteoblast and impaired
osteoclast elements.PYK2 is one member of a family of over 500 evolutionarily conserved enzymes
with high amino acid and structural conservation within the catalytic ATP
binding pocket. Classical kinase inhibitors bind to the ATP site and compete
for substrate binding. Thus, while classical inhibitors based on ATP binding
analogs have been readily identified, the inherent promiscuity of action for
this class has presented significant challenges to drug design
(8). With the exception of
cancer therapeutics, where additional therapeutic benefits may be gained by
the inhibition of multiple kinase targets (e.g. Sutent, Sorafenib),
minimizing off-target activity is most often desired. Therefore, there is
great interest in identifying unique allosteric regulatory domains for
specific kinase targets. Despite intense effort, small molecule inhibitors
exploiting extra-catalytic allosteric sites have been limited to a few
examples including IKK (9) and
MEK (10). Alternatively,
bipartite inhibitors have been developed that stabilize an inactive
conformation of the protein kinase, the prototypical example being BIRB796
binding to p38 and Gleevec binding to Abl. Such compounds make contact with
both the conserved ATP site and less conserved regions of the activation loop,
thus offering the potential for improved selectivity
(11). The N terminus of the
activation loop contains an invariant Asp-Phe-Gly (DFG) motif, and is an
important determinant of enzyme activity. In the active or
“DFG-in” conformation, these amino acids are involved in the
coordination of ATP. Conversely, the “DFG-out” state does not bind
ATP and the kinase is inactive. While a handful of kinases are known to adopt
a DFG-out conformation (e.g. p38, Abl, etc), it remains to be
determined how general this strategy might be in the design of selective
kinase inhibitors.To help elucidate the molecular mechanism of PYK2 and its substrate
specificity, we used biophysical methods and determined multiple x-ray
structures of the PYK2 kinase domain. High-resolution structures of apo and
ATPγS-bound forms were obtained as well as a complex with PF-431396, a
“classical” kinase inhibitor. Empirical screening identified
BIRB796 as a weak PYK2 kinase inhibitor. Surface plasmon resonance (SPR) and
NMR studies indicated that PYK2 could adopt a “DFG-out”
conformation. Despite the low affinity, a 1.75-Å co-crystal structure
was obtained with BIRB796 revealing a novel binding mode. Our biophysical and
structural results provide insight into the enzyme-substrate complex and
allowed us to advance the rational design of a selective DFG-out inhibitor
with improved PYK2 selectivity and potency. The compound, PF-4618433, showed
robust osteogenic activity in hMSC cultures. 相似文献
66.
Maria A. Nilsson Gennady Churakov Mirjam Sommer Ngoc Van Tran Anja Zemann Jürgen Brosius Jürgen Schmitz 《PLoS biology》2010,8(7)
The Australasian and South American marsupial mammals, such as kangaroos and opossums, are the closest living relatives to placental mammals, having shared a common ancestor around 130 million years ago. The evolutionary relationships among the seven marsupial orders have, however, so far eluded resolution. In particular, the relationships between the four Australasian and three South American marsupial orders have been intensively debated since the South American order Microbiotheria was taxonomically moved into the group Australidelphia. Australidelphia is significantly supported by both molecular and morphological data and comprises the four Australasian marsupial orders and the South American order Microbiotheria, indicating a complex, ancient, biogeographic history of marsupials. However, the exact phylogenetic position of Microbiotheria within Australidelphia has yet to be resolved using either sequence or morphological data analysis. Here, we provide evidence from newly established and virtually homoplasy-free retroposon insertion markers for the basal relationships among marsupial orders. Fifty-three phylogenetically informative markers were retrieved after in silico and experimental screening of ∼217,000 retroposon-containing loci from opossum and kangaroo. The four Australasian orders share a single origin with Microbiotheria as their closest sister group, supporting a clear divergence between South American and Australasian marsupials. In addition, the new data place the South American opossums (Didelphimorphia) as the first branch of the marsupial tree. The exhaustive computational and experimental evidence provides important insight into the evolution of retroposable elements in the marsupial genome. Placing the retroposon insertion pattern in a paleobiogeographic context indicates a single marsupial migration from South America to Australia. The now firmly established phylogeny can be used to determine the direction of genomic changes and morphological transitions within marsupials. 相似文献
67.
Peter C. Bonnette Brett S. Robinson Jeffrey C. Silva Matthew P. Stokes Arthur D. Brosius Amy Baumann Leonard Buckbinder 《Journal of Proteomics》2010,73(7):1306-1320
The PYK2 tyrosine kinase is a negative regulator of bone formation, but aside from the requirement for PYK2 kinase activity there has been little progress toward understanding of the molecular mechanism involved in this function. To gain insight into the signaling pathways modulated by PYK2 we sought to identify PYK2 substrates. Challenges inherent to a quantitative phosphoproteomic analysis for non-receptor tyrosine kinases were overcome by employing an inducible PYK2 overexpression system in NIH3T3 cells in combination with a selective PYK2 inhibitor. The identification of a number of known PYK2 substrates and interacting partners validated the methodology. Results of the inducible cell system were extended to a cell model of osteogenesis, examining the effect of the PYK2 inhibitor on the phosphorylation state of targets identified in the phosphoproteomic study. Consistent with phosphoproteomic analysis, increased osteogenesis associated with a selective PYK2 inhibitor was accompanied by reduced phosphorylation of paxillin, Gab1 and p130Cas, along with reduction of phosphorylation levels of the Met activation loop. These results further confirmed the utility of the methodology and point to a previously unknown bi-directional activation pathway between PYK2 and Met. 相似文献
68.
Carsten A. Raabe Cecilia P. Sanchez Gerrit Randau Thomas Robeck Boris V. Skryabin Suresh V. Chinni Michael Kube Richard Reinhardt Guey Hooi Ng Ravichandran Manickam Vladimir Y. Kuryshev Michael Lanzer Juergen Brosius Thean Hock Tang Timofey S. Rozhdestvensky 《Nucleic acids research》2010,38(2):608-617
69.
70.
Maja Bulatovi? ?alasan Oscar FC van den Bosch Marjonne CW Creemers Martijn Custers Antonius HM Heurkens Jan Maarten van Woerkom Nico M Wulffraat 《Arthritis research & therapy》2013,15(6):R217