Focal Adhesion Kinase (FAK) is a major cancer drug target that is involved in numerous aspects of tumor progression and survival. While multiple research groups have developed ATP-competitive small molecule inhibitors that target the kinase enzyme, recent attention has been focused on the FAK FERM (Band 4.1, Ezrin, Radixin, Moesin) domain that contains key residue Y397 and contributes to many protein-protein interactions. Previous x-ray crystal structures of the FAK FERM domain gave conflicting results on the structure of the Y397 region and therefore the overall druggability. Here, we report the identification of a higher resolution crystal structure of the avian FAK FERM domain that shows conformational differences in Y397 and surrounding residues in the F1 lobe. In addition, we resolve the residues of the Src SH3 binding site, an area of the FERM domain that has previously shown limited electron density. These crystallographic data suggest that the Y397 region is highly dynamic and question the druggability of a putative pocket on the F1 lobe. In addition, new electron density data around the Src SH3 binding site provide structural insight on the FAK-Src activation cascade through a putative auto-inhibitory conformation.

中文翻译：

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FAK FERM域的高分辨率晶体结构揭示了酪氨酸397和Src SH3结合位点的可塑性的新见解

粘着斑激酶（FAK）是一种主要的癌症药物靶标，涉及肿瘤进展和生存的许多方面。虽然多个研究小组已经开发出了针对激酶酶的具有ATP竞争能力的小分子抑制剂，但最近的注意力集中在FAK FERM（4.1频段，Ezrin，Radixin，Moesin）结构域上，该结构域包含关键残基Y397，并有助于许多蛋白质-蛋白质互动。FAK FERM域的先前X射线晶体结构在Y397区域的结构上给出了矛盾的结果，因此在总体可药物性上给出了矛盾的结果。在这里，我们报告鉴定禽FAK FERM域的更高分辨率的晶体结构，该结构显示Y397和F1叶片周围残基的构象差异。此外，我们解析了Src SH3结合位点的残基，先前显示有限电子密度的FERM域区域。这些晶体学数据表明，Y397区域是高度动态的，并质疑F1瓣上推定口袋的可吸性。此外，Src SH3结合位点周围的新电子密度数据通过推定的自动抑制构象提供了有关FAK-Src激活级联的结构见解。