Behnen Petra, Felline Angelo, Comitato Antonella, Di Salvo Maria Teresa, Raimondi Francesco, Gulati Sahil, Kahremany Shirin, Palczewski Krzysztof, Marigo Valeria, Fanelli Francesca
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy.
Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
iScience. 2018 Jun 29;4:1-19. doi: 10.1016/j.isci.2018.05.001. Epub 2018 May 5.
The autosomal dominant form of retinitis pigmentosa (adRP) is a blindness-causing conformational disease largely linked to mutations of rhodopsin. Molecular simulations coupled to the graph-based protein structure network (PSN) analysis and in vitro experiments were conducted to determine the effects of 33 adRP rhodopsin mutations on the structure and routing of the opsin protein. The integration of atomic and subcellular levels of analysis was accomplished by the linear correlation between indices of mutational impairment in structure network and in routing. The graph-based index of structural perturbation served also to divide the mutants in four clusters, consistent with their differences in subcellular localization and responses to 9-cis retinal. The stability core of opsin inferred from PSN analysis was targeted by virtual screening of over 300,000 anionic compounds leading to the discovery of a reversible orthosteric inhibitor of retinal binding more effective than retinal in improving routing of three adRP mutants.
常染色体显性遗传性视网膜色素变性（adRP）是一种致盲的构象疾病，在很大程度上与视紫红质的突变有关。结合基于图的蛋白质结构网络（PSN）分析的分子模拟和体外实验，以确定33种adRP视紫红质突变对视蛋白结构和信号传导途径的影响。通过结构网络和信号传导途径中突变损伤指标之间的线性相关性，实现了原子水平和亚细胞水平分析的整合。基于图的结构扰动指标也用于将突变体分为四类，这与它们在亚细胞定位和对9-顺式视黄醛反应方面的差异一致。通过对30多万种阴离子化合物进行虚拟筛选，靶向PSN分析推断出的视蛋白稳定性核心，从而发现一种可逆的视网膜结合正构抑制剂，在改善三种adRP突变体的信号传导途径方面比视黄醛更有效。
