School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Department of Biochemistry and Molecular Pharmacology New York University School of Medicine, New York, NY 10016, USA.
Structure. 2013 Oct 8;21(10):1889-96. doi: 10.1016/j.str.2013.07.017. Epub 2013 Aug 22.
The K650E gain-of-function mutation in the tyrosine kinase domain of FGF receptor 3 (FGFR3) causes Thanatophoric Dysplasia type II, a neonatal lethal congenital dwarfism syndrome, and when acquired somatically, it contributes to carcinogenesis. In this report, we determine the crystal structure of the FGFR3 kinase domain harboring this pathogenic mutation and show that the mutation introduces a network of intramolecular hydrogen bonds to stabilize the active-state conformation. In the crystal, the mutant FGFR3 kinases are caught in the act of trans-phosphorylation on a kinase insert autophosphorylation site, emphasizing the fact that the K650E mutation circumvents the requirement for A-loop tyrosine phosphorylation in kinase activation. Analysis of this trans-phosphorylation complex sheds light onto the determinants of tyrosine trans-phosphorylation specificity. We propose that the targeted inhibition of this pathogenic FGFR3 kinase may be achievable by small molecule kinase inhibitors that selectively bind the active-state conformation of FGFR3 kinase.
成纤维细胞生长因子受体 3（FGFR3）酪氨酸激酶结构域的 K650E 功能获得性突变导致致死性先天性侏儒综合征 II 型，当获得性体细胞突变时，它会促进癌发生。在本报告中，我们确定了携带这种致病突变的 FGFR3 激酶结构域的晶体结构，并表明该突变引入了一个分子内氢键网络，以稳定活性构象。在晶体中，突变的 FGFR3 激酶被捕获在激酶插入自身磷酸化位点上的反式磷酸化过程中，这强调了 K650E 突变绕过了激酶激活中 A 环酪氨酸磷酸化的要求。对该反式磷酸化复合物的分析揭示了酪氨酸反式磷酸化特异性的决定因素。我们提出，通过选择性结合 FGFR3 激酶的活性构象的小分子激酶抑制剂，可能实现针对这种致病性 FGFR3 激酶的靶向抑制。
