Christensen Nikolaj R, Čalyševa Jelena, Fernandes Eduardo F A, Lüchow Susanne, Clemmensen Louise S, Haugaard-Kedström Linda M, Strømgaard Kristian
Center for Biopharmaceuticals Department of Drug Design and Pharmacology University of Copenhagen Universitetsparken 2 2100 Copenhagen Denmark.
European Molecular Biology Laboratory (EMBL) Structural and Computational Biology Unit Meyerhofstraße 1 69117 Heidelberg Germany.
Adv Ther (Weinh). 2019 Jul;2(7):1800143. doi: 10.1002/adtp.201800143. Epub 2019 Apr 24.
Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.
蛋白质网络中的蛋白质-蛋白质相互作用塑造了人类相互作用组，这一过程通常由专门的蛋白质相互作用模块促进，例如突触后致密蛋白95（PSD-95）、盘状大蛋白、紧密连接蛋白1（ZO-1）（PDZ）结构域。PDZ结构域在多种细胞功能中发挥作用，从细胞间通讯和极化到蛋白质转运和蛋白质代谢的调节。PDZ结构域蛋白在蛋白质复合物的形成和稳定性方面也至关重要，在跨膜受体检测到的细胞外刺激与细胞内反应之间建立了重要桥梁。PDZ结构域已被认为是多种疾病中有前景的药物靶点，范围从神经和肿瘤疾病到病毒感染。在这篇综述中，作者描述了含PDZ蛋白的结构和遗传学方面，并讨论了PDZ结构域小分子和肽调节剂的开发现状。还提供了PDZ介导的蛋白质网络中潜在新治疗干预措施的概述。
