Ephrins structure

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. 

Fig. 2. Structures of the extracellular domains of Ephs and ephrins. The molecular surfaces (semi-transparent) are also indicated. (A) Structure of the ligand-binding domain of EphB2. The N- and C-termini of the molecule are labeled, as are the class-specificity loop (H-I) and the ligand-binding loops that are largely disordered in the absence of bound ephrin. (B) Structure of the extracellular receptor-binding domain of ephrin-B2. Indicated is the location of the receptor-binding G-H loop. (C) Structure of the EphB2/ephrin-B2 tetramer. Eph receptors are blue and ephrins are green. The high-affinity dimerization interfaces are indicated by arrows. (See Color Insert.)...

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

The solution structure of the cytoplasmic domain of human ephrin-B2 was also determined (Song et al, 2002) and revealed that the 48 N-terminal ephrin residues are unstructured and are prone to aggregation. The highly conserved 33 C-terminal residues, on the other hand, form a well-packed hairpin structure followed by the flexible PDZ-binding tail. 

Fig. 4. Structures of the Eph/ephrin intra- and inter-subclass heterodimers. (A) Structure of the EphB2 (right)/ephrin-B2 (left) high-affinity heterodimer. The N- and C-termini of the molecules are indicated. (B) Structure of the complex between EphB2 and ephrin-A5 in the same orientation as in (A). The arrows indicate the changes in the relative ligand and receptor positions between the intra- and inter-subclass complexes.

Himanen, J.-P. et al. (2001). Crystal structure of an Eph receptor-ephrin complex. Nature 414, 933-938. 

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. 

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. 

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