Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard, College Station, TX, 77843, United States.
Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Boulevard, College Station, TX, 77843, United States.
Adv Biol Regul. 2021 Jan;79:100784. doi: 10.1016/j.jbior.2020.100784. Epub 2021 Jan 18.
Protein Kinase C isoenzymes (PKCs) are the key mediators of the phosphoinositide signaling pathway, which involves regulated hydrolysis of phosphatidylinositol (4,5)-bisphosphate to diacylglycerol (DAG) and inositol-1,4,5-trisphosphate. Dysregulation of PKCs is implicated in many human diseases making this class of enzymes an important therapeutic target. Specifically, the DAG-sensing cysteine-rich conserved homology-1 (C1) domains of PKCs have emerged as promising targets for pharmaceutical modulation. Despite significant progress, the rational design of the C1 modulators remains challenging due to difficulties associated with structure determination of the C1-ligand complexes. Given the dearth of experimental structural data, computationally derived models have been instrumental in providing atomistic insight into the interactions of the C1 domains with PKC agonists. In this review, we provide an overview of the in silico approaches for seven classes of C1 modulators and outline promising future directions.
蛋白激酶 C 同工酶（PKCs）是磷酸肌醇信号通路的关键介质，该通路涉及磷脂酰肌醇（4,5）-二磷酸的调节水解为二酰基甘油（DAG）和肌醇-1,4,5-三磷酸。PKCs 的失调与许多人类疾病有关，使这类酶成为重要的治疗靶点。具体来说，PKCs 的 DAG 感应富含半胱氨酸的保守同源性-1（C1）结构域已成为药物调节的有前途的靶点。尽管取得了重大进展，但由于与 C1-配体复合物的结构确定相关的困难，C1 调节剂的合理设计仍然具有挑战性。鉴于实验结构数据的缺乏，计算得出的模型在提供 C1 结构域与 PKC 激动剂相互作用的原子水平洞察力方面发挥了重要作用。在这篇综述中，我们概述了七类 C1 调节剂的计算方法，并概述了有前途的未来方向。
