A628T TEV

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 受体酪氨酸激酶参与多种过程，包括细胞增殖、分化、迁移、伤口愈合、神经突生长和细胞-细胞通讯。 成纤维细胞生长因子受体（FGFR），特别是，已涉及多种人类骨骼发育不良，包括侏儒软骨发育和颅缝早闭综合征。 近年来发现FGFR 2激酶结构域的突变，导致泪腺-耳-牙-指（拉德）综合征。 这种疾病的特征是泪腺和唾液腺的异常以及耳朵、牙齿和手指的畸形。 一个突变A628 T位于催化核心，即磷酸转移位点，另外两个突变A648 T和R649 del 650位于激酶的激活环中。 生化证据表明，这些突变是功能缺失突变，在本项目中，我们的目的是通过获得携带A628 T点突变的FGFR 2激酶结构域的高分辨率晶体结构来了解这种失活的机制。 深入了解这种突变如何影响激酶活性可能会揭示一些点突变如何导致robost激活，而另一些则导致催化活性丧失。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Receptor tyrosine kinases are involved in diverse processes including cell proliferation, differentiation, migration, wound healing, neurite outgrowth, and cell-cell communication. Fibroblast growth factor receptors (FGFR), in particular, have been implicated in multiple human skeletal dysplasias including dwarfing chondroplasias and craniosynostosis syndromes. Recently, mutations in FGFR2 kinase domain were discovered, which result in Lacrimo-auriculo-dento-digital (LADD) syndrome. This disease is characterized by abnormalities in the lacrimal and salivary glands and malformation of the ears, teeth, and digits. One mutation, A628T, resides in the catalytic core, the site of phosphotransfer, and two others, A648T and R649del650, reside in the activation loop of the kinase. Biochemical evidence suggests that these mutations are loss of function mutations, and in this project, we aimed to understand the mechanism of this inactivation by obtaining a high resolution crystal structure of FGFR2 kinase domain harboring an A628T point mutation. Insight into the how this mutation affects kinase activity may shed light on how some point mutations cause robost activation while others result in loss of the catalytic activity.