Structure and thermodynamic characterization of the EphB4/ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity
Structure and thermodynamic characterization of the EphB4/ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity
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DOI：
10.1016/j.str.2005.11.011
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发表时间：
2006-02-01
期刊：
影响因子：
5.7
通讯作者：
Kuhn, P
中科院分区：
文献类型：
--
作者：
Chrencik, JE;Brooun, A;Kuhn, P
Eph受体酪氨酸激酶及其配体，即肾上腺素，调节着发育中和成人组织中的许多生物学过程，并与癌症的进展和血管生成的病理形式有关。我们报道了EphB4受体与一种高度特异的拮抗肽的络合物的晶体结构，其分辨率为1.65埃。该多肽位于EphB4的疏水裂隙中，对应于EphB2中被ePhin-132G-H环占据的裂隙，与其拮抗特性一致。结构分析确定了EphB4结合裂隙中的几个残基，这些残基可能决定了该受体的配体特异性，而对截短形式的多肽进行的等温滴定量热实验定义了多肽中对受体结合至关重要的氨基酸残基。这些研究揭示了结构特征，这将有助于药物发现计划开发用于治疗应用的EphB4拮抗剂。
The Eph receptor tyrosine kinases and their ligands, the ephrins, regulate numerous biological processes in developing and adult tissues and have been implicated in cancer progression and in pathological forms of angiogenesis. We report the crystal structure of the EphB4 receptor in complex with a highly specific antagonistic peptide at a resolution of 1.65 angstrom. The peptide is situated in a hydrophobic cleft of EphB4 corresponding to the cleft in EphB2 occupied by the ephrin-132 G-H loop, consistent with its antagonistic properties. Structural analysis identifies several residues within the EphB4 binding cleft that likely determine the ligand specificity of this receptor, while isothermal titration calorimetry experiments with truncated forms of the peptide define the amino acid residues of the peptide that are critical for receptor binding. These studies reveal structural features that will aid drug discovery initiatives to develop EphB4 antagonists for therapeutic applications.