Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, USA.
IUBMB Life. 2019 Jun;71(6):706-720. doi: 10.1002/iub.2060. Epub 2019 May 2.
Intercellular communication governs complex physiological processes ranging from growth and development to the maintenance of cellular and organ homeostasis. In nearly all metazoans, receptor tyrosine kinases (RTKs) are central players in these diverse and fundamental signaling processes. Aberrant RTK signaling is at the root of many developmental diseases and cancers and it remains a key focus of targeted therapies, several of which have achieved considerable success in patients. These therapeutic advances in targeting RTKs have been propelled by numerous genetic, biochemical, and structural studies detailing the functions and molecular mechanisms of regulation and activation of RTKs. The latter in particular have proven to be instrumental for the development of new drugs, selective targeting of mutant forms of RTKs found in disease, and counteracting ensuing drug resistance. However, to this day, such studies have not yet yielded high-resolution structures of intact RTKs that encompass the extracellular and intracellular domains and the connecting membrane-spanning transmembrane domain. Technically challenging to obtain, these structures are instrumental to complete our understanding of the mechanisms by which RTKs are activated by extracellular ligands and of the effect of pathological mutations that do not directly reside in the catalytic sites of tyrosine kinase domains. In this review, we focus on the recent progress toward obtaining such structures and the insights already gained by structural studies of the subdomains of the receptors that belong to the epidermal growth factor receptor, insulin receptor, and platelet-derived growth factor receptor RTK families. © 2019 IUBMB Life, 71(6):706-720, 2019.
细胞间通讯控制着从生长和发育到细胞和器官稳态维持的复杂生理过程。在几乎所有的后生动物中，受体酪氨酸激酶（RTKs）是这些多样化和基本信号转导过程的核心参与者。异常的 RTK 信号是许多发育疾病和癌症的根源，它仍然是靶向治疗的重点，其中一些在患者中取得了相当大的成功。这些针对 RTK 的治疗进展得益于许多遗传、生化和结构研究，这些研究详细描述了 RTKs 的功能和调节及激活的分子机制。特别是后者已被证明对于开发新药物、选择性针对疾病中发现的 RTK 突变形式以及对抗随之而来的耐药性至关重要。然而，迄今为止，这些研究尚未获得完整 RTKs 的高分辨率结构，这些结构包含细胞外和细胞内结构域以及连接的跨膜结构域。这些结构难以获得，对于我们完整理解 RTKs 如何被细胞外配体激活的机制以及不直接位于酪氨酸激酶结构域催化位点的病理性突变的影响至关重要。在这篇综述中，我们重点介绍了获得这些结构的最新进展，以及对属于表皮生长因子受体、胰岛素受体和血小板衍生生长因子受体 RTK 家族的受体亚基的结构研究已经获得的见解。©2019 IUBMB Life，71(6):706-720，2019。
