Protein kinase fragment

Figure 36-25. Double-strand break repair of DNA. The proteins Ku and DNA-dependent protein kinase combine to approximate the two strands and unwind them. The aligned fragments form base pairs the extra ends are removed, probably by a DNA-PK-associated endo- or exonuclease, and the gaps are filled in and continuity is restored by ligation.

Fig. 1.6 The increase in potency of a 1.3 mM p38 a protein kinase-binding fragment inhibitor identified by X-ray screening through the major changes made to the chemical series to exploit key binding features within the active site.

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Kanter P, Leister KJ, Tomei LD, Wenner PA, Wenner CE (1984) Epidermal growth factor and tumor promoters prevent DNA fragmentation by different mechanisms. Biochem Biophys Res Commun 118 392-399 Kariya K-I, Kawahara Y, Tsuda T (1987) Possible involvement of protein kinase C in platelet-derived growth factor-stimulated DNA synthesis in vascular smooth musde cells. Atherosderosis 83 251-255... 

McConkey DJ, Hartzell P, Jondal M, Orrenius S (1989) Inhibition of DNA fragmentation in thymocytes and isolated thymocyte nuclei by agents that simulate protein kinase C.) Biol Chem 264 13399-13402 McConkey DJ, Nicotera P, Orrenius S (1994) Signalling and chromatin fragmentation in thymocyte apoptosis. Immunol Rev 142 343-363 McCoy C, Smith DE, Cornwell MM (1995) 12-0-tetradecanoylphorbol-13-acetate activation of the MDRl promoter is mediated by EGRl. Mol Cell Biol 15 6100-6108... 

Shape constrained natural compounds (tocopherol homologues, vitamin E)" protein kinase ZAP-70 tryptic fragment containing amino acids 485 96 cartenoids from a spinach sample isoflavines in Radix astragali ... 

Fig. 7.2. Structure and substrate binding sites of Ser/Thr-spedfic protein kinases, a) Peptide binding site structure of the catalytic subunit of the cAMP-dependent protein kinase A from mouse, with bound inhibitor peptide PKI (5-22), shown in dark in the figure. PKI (5-22) is a fragment (amino adds 5-22) of the naturally occurring heat-stable protein kinase inhibitor PKI. The inhibitor peptide binds in the region of the substrate binding site between the two lobes of protein kinase A (Knighton et al., 1991). The P-loop is involved in binding the phosphate residue of ATP. b) ATP binding site structure of casein kinase I with bound Mg-ATP. The Mg is shown as a sphere. MOLSKRIPT representation according to Kraulis, (1991).

Structural information on autoinhibition is available for the twitchin kinase. The twitchin kinase is a Ser/Thr-specific protein kinase of the nematode Caenorhabditis ele-gans and is homologous to the myosin light chain kinase of mammals (see 7.4.1). The crystal structure of a catalytic fragment of twitchin kinase (Hu et al., 1994) has an auto-inhibitory element at the C-terminus, which makes specific contact with parts of the active site and the ATP binding site. The active site of twitchin kinase is blocked by the autoinhibitory structural element by ... 

Jarvis, W.D., Turner, A.J., Povirk, L.F., Traylor, R.S., and Grant, S., Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C, Cancer Res., 54, 1707, 1994. 

Gill, A. (2004). New lead generation strategies for protein-kinase inhibitors - fragment based screening approaches. Mini-Reviews in Medicinal Chemistry 4, 301-11. 

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