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Crystal structure of the human ephrin‐A5 ectodomain
Author(s) -
Nikolov Dimitar,
Li Chen,
Lackmann Martin,
Jeffrey Philip,
Himanen Juha
Publication year - 2007
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.062665807
Subject(s) - ephrin , erythropoietin producing hepatocellular (eph) receptor , eph receptor a2 , ectodomain , receptor , biophysics , plasma protein binding , chemistry , biology , microbiology and biotechnology , receptor tyrosine kinase , stereochemistry , biochemistry
The Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell–cell communication regulating cell attachment, pathfinding, and mobility in the nervous and cardiovascular systems. Recent structural studies have revealed unique molecular features that explain many of the biochemical and signaling properties of Ephs and ephrins. Nevertheless, open questions remain, including understanding the precise molecular mechanism underlining their binding‐partner preferences and subclass specificity. In this study, we have determined and present the crystal structure of the extracellular domain of ephrin‐A5—the first structure of an unbound A‐class ephrin. The structure, determined at 2.1 Å resolution, is a variation of the Greek key β‐barrel folding topology, containing eight β‐strands, and stabilized by two disulphide bonds. Overall, ephrin‐A5 is structurally very similar to ephrin‐B1 and ephrin‐B2 but, unlike ephrin‐B2, it does not show dimerization either in solution or in the crystals. Comparing free ephrin‐A5 to the previously published structure of EphB2‐bound ephrin‐A5 reveals that significant conformational changes occur only around the G–H ephrin loop that upon binding bends toward the receptor. Interestingly, the G–H loop undergoes a very similar conformational rearrangement in ephrin‐B2 upon receptor binding. The results of this study further emphasize the importance of the G–H loop for receptor recognition and selectivity, and could serve as a starting point for the development of structure‐based Eph antagonists.