Eph kinases

Myshkin, E. and Wang, B. Chemometrical classification of ephrin ligands and eph kinases using GRID/CPCAapproach./. Chem. Inf. Comput. Sci. 2003, 43, 1004-1010. 

Eph receptor tyrosine kinases play a crucial role in intercellular processes such as angiogenesis, neurogenesis, and carcinogenesis. Based on their affinity for ephrin ligands, the Eph kinases are divided into two subfamilies, EphA and EphB, which bind to ephrinA and ephrinB, respectively [60]. 

In the resulting score plot, the first PC discriminated between the ephrins and the Eph kinases, which is in agreement with the complementary nature of interactions between these proteins. A separate classification of the kinases and ligands clearly showed two clusters corresponding to the A and B subfamilies. Kinases with a unique biological interaction profile showed up as outliers in the score plot. 

Subsequently, the authors analyzed the structural basis of the eph-Eph kinase interaction. The differential plots for the cluster of Eph kinases and the cluster of ephrins, highlighted the complementary binding regions, i.e. areas of favorable interaction between kinase and ligand. Additionally, the differences between the... 

However, a number of biological findings could not be explained by the CPCA analysis. The authors attribute this to the fact that the ephrin-Eph kinase interactions are best described by an induced fit mechanism. The necessary computational assumption of keeping the protein structure rigid did not reflect the flexibility of the protein interfaces and their structural adaptability. The homology models, on the other hand, provided a rigid protein structure that is biased by the template protein EphB2. 

E. Myshkin, B. Wang, Chemometrical classification of ephrin ligands and Eph kinases using GRID/CPCA approach,... 

Ephrins are a group of membranous ligands, which function through a family of receptor tyrosine kinases (Ephs). Ephrin/Eph-mediated signaling processes are involved in morphogenetic processes taking place e.g. during the development of the nervous system or the vasculature. 

Drescher, U., Kremoser, C., Handwerker, C. et al. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82 359-370,1995. 

Hirai, H.,Maru,Y.,Hagiwara,K. etal. A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238 1717-1720, 1987. 

Fig. 5. Structures of the intracellular domains of Eph receptors. (A) Structure of the EphB2 kinase domain autoinhibited by the nonphosphorylated juxtamembrane region. The C-terminal kinase lobe is green and the N-terminal lobe is brown. The two regulatory tyrosine residues in the blue juxtamembrane region are shown in red. The ATP location in the active site is indicated in gray. (B) Structure of the monomeric sterile a motif (SAM) domain of EpliA4. Reproduced with permission from (Himanen et al, 2003b). (See Color Insert.)...

Davis, S. et al. (1994). Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266, 816-819. 

Lackmann, M. et al (1997). Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor. /. Biol Chem. 272, 16521-16530. 

Ephrins Ephrins may be involved in celF-cell signalling Eph-like receptors Tyrosine kinases... 

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