同源建模构建ABLSH3突变体及其与RIN1蛋白结合能力的分析  

Analysis of Binding Capacity Between Homology Modeling of ABLSH3 Mutants and RIN1 Protein

作　　者：刘鑫[1] 崔淼淼 付珮一[1] 黄凌[1] 徐方明[1] 

机构地区：[1]贵州省人民医院检验科,贵州贵阳550004 [2]贵阳市第二人民医院检验科,贵州贵阳550004

出　　处：《药物生物技术》2016年第4期345-348,共4页Pharmaceutical Biotechnology

摘　　要：Bcr-Abl SH3与RIN1富含脯氨酸的序列结合,激活Bcr-Abl酪氨酸激酶活性,引起慢粒患者对伊马替尼耐药,为改变两者结合方式解决耐药问题,笔者对Bcr-Abl SH3结构域活性位点进行分析。Pep Site2.0软件分析RIN1与Bcr-Abl SH3结合部位及特点,选择突变位点,VMD1.8.7和NAMD2.6软件动态模拟获取稳定的SH3突变体结构,Pep Site2.0分析突变体和RIN1结合能力大小。两者结合部位位于SH3 90-118氨基酸位点,3种突变方式中双位点突变效果明显优于单位点及缩短的片段,单位点突变中并非所有被选择的位点突变后结合能力都提高,说明RIN1与SH3结合不仅依赖结合部位的特异氨基酸,其周围的氨基酸对维持两者的结合有着至关重要的作用。RIN1 protein with a proline-rich region can bind to Bcr-Abl SH3 domain to activate tyrosine kinase of Bcr-Abl,and induce the resistance to imatinib（ IM）. Then,the active sites of SH3 domain were analyzed in order to change the mode of action with RIN1 as well as solve resistance in chronic myeloid leukemia（ CML）. Firstly,the amino acids sequence characteristic at active site of SH3 domain and was analyzed by Pep Site2. 0 for understanding the distribution of amino acids in the combined action. Then amino acids were located binding sites of SH3 domain were selectively mutated base on the P-values. There are three methods of mutation style： single site mutation,combinations of single mutation,shortened Abl SH3 domain and reserved binding position,as well as mutants＇ structure were modelled by using NAMD2. 8 and VMD1. 8. 7 software. It was interesting that amino acids around the binding site had an important role in the maintenance of binding between proteins and ligands. The combination of both RIN1 and SH3 depended not only on the specific amino acid sites,but also the amino acids surrounding had a vital role in maintaining both of combination.

关 键 词：同源建模 BCR-ABL SH3结构域 RIN1蛋白 PEP Site2.0 NAMD2.8 VMD1.8.7. 

分 类 号：Q81[生物学—生物工程]