标题: | 区域官能基地图揭露人类蛋白激酶之选择性与机制 Site-moiety maps reveal the selectivity and mechanisms of human protein kinases |
作者: | 尤宣人 You, Syuan-Ren 杨进木 Yang, Jinn-Moon 分子医学与生物工程研究所 |
关键字: | 蛋白激酶;药物设计;kinases;drug design |
公开日期: | 2011 |
摘要: | 蛋白激酶在讯息传递途径上扮演重要角色,蛋白激酶若失去调控将引发一些复杂疾病,这使蛋白激酶成为许多疾病治疗的热门标的,如癌症、糖尿病、神经失调、心血管疾病等。由于518个人类蛋白激酶多具有演化上高度保留的ATP结合位,所以大多数的蛋白激酶抑制剂皆与多种蛋白激酶交互作用,这使得设计选择性蛋白激酶抑制剂成为新兴且极具挑战的任务。 我们提出“激酶-抑制剂家族(KIF)”这个新概念,希望能有助于探讨蛋白激酶选择性与机制。我们共建构了775个KIFs,包含171,265个蛋白激酶-抑制剂交互作用、37,601个蛋白激酶抑制剂和518个人类蛋白激酶。对一个KIF中的蛋白激酶成员而言,我们用14个锚点之区域官能基地图(SiMMap)来探讨保留的蛋白激酶子结构环境与其抑制剂一致的化学官能基之间的交互作用。SiMMap中一致的锚点是子结构环境与化学官能基之间的交互作用在统计上具有显着性,可被视为一个热点,代表此保守的结合环境除了参与抑制剂结合外,还具生物功能。KIF的定义为:(1)蛋白激酶序列显着相似(BLAST E-value ≤ 10-40)、(2)抑制剂之拓朴构型与官能基组成显着相似、(3)蛋白激酶-抑制剂之结合介面(kinase-inhibitor binding interfaces)与交互作用力(interaction)相似。 透过大规模蛋白激酶分析的实验结果显示,在同一KIF中的蛋白激酶通常拥有相似的抑制剂。更进一步还发现SiMMap能区别不同的蛋白激酶构型,例如DFG-in, DFG-out, A-loop active, A-loop inactive,且与抑制剂选择性有关,例如第一型抑制剂与第二型抑制剂。在我们收集的638个与疾病相关之残基突变的实验资料显示,区域官能基地图所辨识出的重要残基(key residue)如果突变常常产生抗药性。我们建构KIDFamMap资料库来表达KIF以及激酶-抑制剂-疾病(KID)的关系,希望可以了解蛋白激酶选择性与机制。此资料库包含775个KIFs、962 个KIDs、171,265个蛋白激酶-抑制剂交互作用、37,601个蛋白激酶抑制剂、518个人类蛋白激酶、339个疾病以及638个与疾病相关之突变。我们相信KIF与KIDFamMap有助于提供生物见解与窥探蛋白激酶选择性及机制。 Protein kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases, such as cancer, diabetes, neuronal disorder and cardiovascular disease. Designing selective protein kinase inhibitors is an emergent and challenge task because 518 human protein kinases share an evolutionary conserved ATP-binding site and the majority of protein kinase inhibitors interact with multiple protein kinases. Here, we proposed a new concept “kinase-inhibitor family (KIF)” for protein kinase selectivity and mechanisms. We have constructed 775 KIFs including 171,265 protein kinase-inhibitor interactions, 37,601 protein kinase inhibitors and 518 human protein kinases. For the protein kinase members in a KIF, we used SiMMap with 14 anchors to discover the conserved structural subsites interacting with consensus moieties of their inhibitors. The consensus anchor, the subsite-moiety interactions with statistical significance, of a SiMMap can be regarded as a ”hot spot” that represents the conserved binding environments involved in inhibitor bindings and biological functions. Here, a KIF can be defined as follows: (1) the protein kinases in a KIF with the significant sequence similarity (BLAST E-value ≤ 10-40); (2) the inhibitors in a KIF with the significant topology and moiety composition similarity; (3) protein kinase-inhibitor interactions in a KIF with similar inhibitions and binding interfaces. Experimental results reveal that the protein kinases and inhibitors in the same KIF often possess the similar inhibitors based on large-scale protein kinase profiling. Furthermore, the SiMMAP anchors are able to reflect protein kinase conformations (e.g., DFG-in, DFG-out, A-loop active, and A-loop inactive), protein kinase functions (638 disease allelic variants are often the conserved interacting residues), and protein kinase selectivity (e.g., Type I, Type II, and Type III inhibitors). We build the KIDFamMap database to represent the KIF and kinase-inhibitor-disease (KID) relationships for protein kinase selectivity and mechanisms. This database includes 775 KIFs, 962 KIDs, 171,265 protein kinase-inhibitor interactions, 37,601 protein kinase inhibitors, 518 human protein kinases, 339 diseases, and 638 disease allelic variants. We believe that KIF and KIDFamMap are useful in providing biological insights and guiding the processes of discovering protein kinase selectivity and mechanisms. |
URI: | http://140.113.39.130/cdrfb3/record/nctu/#GT079929516 http://hdl.handle.net/11536/49982 |
显示于类别: | Thesis |