基于序列-结构分析探讨IL2突变影响肿瘤患者临床生存的作用机制  

Mechanism of IL2 Mutation Affecting Clinical Survival in Cancer Patients Based on Sequence-Structure Analysis

作　　者：许佳红 吉丽娜[1] 李家璜[1,2,3] 华子春 XU Jia-hong;JI Li-na;LI Jia-huang;HUA Zi-chun(The State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing 210023,China;School of Biopharmacy,China Pharmaceutical Universily,Nanjing 211198,China;Changzhou High-Tech Research Institutle of Nanjing University and Jiangsu Target Pharma Laboratories Inc.,Changzhou 213164,China)

机构地区：[1]南京大学生命科学学院医药生物技术国家重点实验室,江苏南京210023 [2]中国药科大学生物药物学院,江苏南京211198 [3]江苏省产业技术研究院医药生物技术研究所常州南京大学高新技术研究院,江苏常州213164

出　　处：《药物生物技术》2022年第3期221-226,共6页Pharmaceutical Biotechnology

基　　金：常州市科技局项目(No.CZ20210010,No.CJ20210024)。

摘　　要：分析临床数据库癌症样本中的IL2突变对其结构功能的影响,探讨内源IL2突变与患者临床生存关联的可能蛋白质作用机制。在cBioPortal数据库不同肿瘤样本中发现29种IL2基因突变,预测表明这些突变大多不利于IL2天然构象的稳定。对皮肤黑色素瘤和子宫内膜癌中的4个IL2变体(P85H、E88K,V111L和V111I)-受体复合物分子动力学模拟,结果表明拥有较高患者生存期的P85H(~62月)和V111L(~89月)突变有利于IL2与IL2β受体的结合,V111L同时提高了IL2结合γ受体的能力,而患者生存期较低的E88K(~37月)和V111I(~23月)突变降低了IL2与IL2β受体结合的能力。推测内源IL2对IL2βγ受体结合作用的强弱可能与肿瘤患者的生存期存在一定正关联。本研究利用计算模拟技术解释了IL2临床突变影响肿瘤患者临床生存的可能作用机制,并为设计新的IL2蛋白药物提供一定的理论借鉴价值。Interleukin2 plays a crucial role in regulating immune activation and homeostasis.It is the first immunotherapy proved to have clinical efficacy in metastatic cancer.To explore the possible protein mechanism of IL2 mutation associated with the clinical survival of patients, the effect of IL2 mutation in cancer samples in the database on its structural function was analyzed.In cBioPortal database, 29 IL2 gene mutations were found in different tumor samples, and the corresponding patient survival was significantly different.Mutation prediction of MOE and mCSM showed that most mutations were not conducive to the stability of the natural conformation of IL2.These mutations may partially affect the natural state of proteins, thereby affecting the role of receptor subunits.Then, Molecular dynamics simulations were performed on four IL2 variants(P85 H,E88 K,V111 L and V111 I)-receptor complexes in cutaneous melanoma and endometrial carcinoma.By comparing the changes of binding free energy between IL2 with its receptors and the changes of IL2 structure after molecular dynamics, the authors found that the P85 H(~62 months) and V111 L(~89 months) with high patient survival favored IL2 binding to IL2 β receptor, and V111 L also improved IL2 binding to IL2 γ receptor.In contrast, the E88 K(~37 months) and V111 I(~23 months) with low patient survival reduced the ability of IL2 to bind to IL2 β receptor.Here, the authors speculate that the binding ability of endogenous IL2 to IL2 R βγ is an important factor affecting the prognosis of patients, and high affinity IL2 R βγ IL2 may be more conducive to the survival of tumor patients.In summary, the binding of endogenous IL2 to IL2 βγ receptor may be positively correlated with the survival time of tumor patients.In this study, computational simulation technology was used to explain the possible mechanism of IL2 clinical mutation affecting the survival of tumor patients.It provides some theoretical reference value for designing new IL2 protein drugs.

关 键 词：cBioPortal数据库 IL2 IL2受体 突变 分子动力学 结构 

分 类 号：R730.5[医药卫生—肿瘤]