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Mechanistic basis for calcium-sensing by the protein-tyrosine kinase 2-beta (PYK2)Momin, Afaque Ahmad Imtiyaz 10 1900 (has links)
The focal adhesion kinase (FAK) and the protein tyrosine kinase 2-beta (PYK2) are two
closely related non-receptor tyrosine kinases that link cell adhesion, migration and
proliferation, and thus also promote cancer cell invasiveness. FAK and PYK2 have the
same domain structure (comprising the FERM, kinase and FAT domains) and possess
several overlapping functions, however their cellular roles can be different or even
opposing. In particular, PYK2 can be activated by calcium, and has important functions in the brain and neurodegenerative disease. The molecular basis for calcium-based activation of PYK2 is unclear and controversial. In this work we combined biophysical and structural methods to determine the molecular basis for calcium-sensing in PYK2.
For this, we investigated the least-studied region of these kinases, namely the long linker (KFL) region between the kinase and FAT domains. This linker is only ~20% conserved between FAK and PYK2, and, therefore, is a prime candidate for causing their differential properties. We find that the linker harbors a helical segment, which is
conserved in both FAK and PYK2, and contributes to their dimerization (an important step in their activation). Helix-flanking regions differ between both proteins, and we show that these of PYK2 create a non-canonical dimeric binding site for calcium-bound calmodulin. Calmodulin-binding is synergistic with linker dimerization in PYK2, explaining how calcium influx can be translated into activation of PYK2. Collectively, our work clarifies the capacities for FAK and PYK2 to receive, process and transduce cellular signals, and may provide new opportunities for targeted therapeutic intervention.
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Targeting Infectious Disease : Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosisJansson, Anna M. January 2013 (has links)
The recent emergence of a number of new viral diseases as well as the re-emergence of tuberculosis (TB), indicate an urgent need for new drugs against viral and bacterial infections. Coronavirus nsp1 has been shown to induce suppression of host gene expression and interfere with host immune response. However, the mechanism behind this is currently unknown. Here we present the first nsp1 structure from an alphacoronavirus, Transmissible gastroenteritis virus (TGEV) nsp1. Contrary to previous speculation, the TGEV nsp1 structure clearly shows that alpha- and betacoronavirus nsp1s have a common evolutionary origin. However, differences in conservation, shape and surface electrostatics indicate that the mechanism for nsp1-induced suppression of host mRNA translation is likely to be different in the alpha- and betacoronavirus genera. The Modoc virus is a neuroinvasive rodent virus with similar pathology as flavivirus encephalitis in humans. The flaviviral methyltransferase catalyses the two methylations required to complete 5´ mRNA capping, essential for mRNA stability and translation. The structure of the Modoc NS5 methyltransferase domain was determined in complex with its cofactor S-adenosyl-L-methionine. The observed methyltransferase conservation between Modoc and other flaviviral branches, indicates that it may be possible to identify drugs that target a range of flaviviruses and supports the use of Modoc virus as a model for general flaviviral studies. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is part of the methylerythritol phosphate (MEP) pathway that produces essential precursors for isoprenoid biosynthesis. This pathway is used by a number of pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, but it is not present in humans. Using a structure-based approach, we designed a number of MtDXR inhibitors, including a novel fosmidomycin-analogue that exhibited improved activity against P.falciparum in an in vitro blood cell growth assay. The approach also allowed the first design of an inhibitor that bridge both DXR substrate and co-factor binding sites, providing a stepping-stone for further optimization.
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