Ephrins with

Inhibitors of the Angiopoietin/Tie-2 and Ephrin/Eph systems are in preclinical development which parallels the biological target validation of these molecules. As vascular assembly, maturation, and homeostasis regulating molecules, therapeutic interference with these molecular systems may hold promise for a number of vascular indications. 

Dolichotheline (111) is a histamine-derived alkaloid produced by the cactus Dolichothele sphaerica Britton and Rose (Cactaceae) native to southern Texas and northern Mexico. The alkaloid was first isolated in 1969 by Rosenberg and Paul (160). Spectroscopic data suggested structure 111, 4(5)-(iV-isovalerylaminoethyl)imidazole or 7V -isovalerylhistamine. The structure was proved by synthesis. Refluxing of histamine with isovaleric anhydride yielded 111, identical to the natural product (160). In addition to the major alkaloid dolichotheline, five minor alkaloids have been isolated (161). These were identified as A-methylphenethylamine, /i-O-methylsyn-ephrine, vV-methyltyramine, synephrine, and / -0-ethylsynephrine by IR, NMR, and comparison to authentic materials / -0-ethylsynephrine was probably an artifact of synephrine, since it was not found in a second extraction attempt when no ethanol was used. 

X-ray crystallographic studies revealed that the ephrin RBD has a globular /3-barrel structure (Fig. 2B) with a Greek key folding topology... 

Himanen et al, 2001 Toth et at, 2001). In the crystals of uncomplexed ephrin-B2, the molecule forms homodimers by burying the hydrophobic surface regions around the G H loop. Since this same loop is involved in receptor binding, the ephrin molecules might exhibit significant rearrangement when their homodimers are displaced upon interaction with the Eph receptors. 

Song, J. et al. (2002). Solution structure and backbone dynamics of the functional cytoplasmic subdomain of human ephrin b2, a cell-surface ligand with bi-directional signaling properties. Biochemistry 41, 10942-10949. 

Torres, R. et al. (1998). PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453-1463. 

It is also important to note that plants house a large group of phytocyanin-related proteins (22 and 24 in Arabidopsis and rice, respectively) that have extensive sequence identity and identical domain architecture to the stellacyanins and uclacyanins but lack the copper-hgating amino acid residues that are crucial for the formation of the type 1 copper site. These copper-free proteins, known as early noduhns, share a common ancestor with metazoan ephrins, which are involved in multiple aspects of embryonal development." " ... 

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. 

---