肿瘤坏死因子与其受体相互作用的计算机模拟研究

The Computer Simulation Study on the InteractionBetween TNF and its Receptors

利用同源模建方法，以ＴＮＦＲ５５受体胞外区的晶体结构为参考模板，预测了ＴＮＦＲ７５受体胞外区Ｃｙｓ１８～Ｐｈｅ１４７片段的三维结构．根据Ｒ５５受体胞外区与ＬＴ相结合的复合物的晶体结构，预测了ＴＮＦ与Ｒ５５及Ｒ７５胞外区的复合物的三维结构，模拟了ＴＮＦ与受体之间的相互作用．由于ＴＮＦ与受体的作用形式是三聚体对三聚体，因此在模拟ＴＮＦ与受体相互作用时选择了包括一个非对称的ＴＮＦ三聚体和一个受体（Ｒ５５或Ｒ７５）单体的模拟系统．结合已有的突变体实验结果，利用计算机模拟分析手段，发现了一些ＴＮＦ突变体之所以具有受体选择性的三维结构基础和发挥了关键作用的氨基酸残基以及这些残基之间的主要作用形式．研究深化了对已有的突变体实验结果的认识，建立了不同的实验结果之间的内在关联，为以后有目的的新型突变体设计和实验研究打下了基础．

Tumor necrosis factorα (TNFα) has been used as an effective agent to kill tumor cells.But wildtype TNFα has rather large side effects.Some experiments showed that the side effects of TNFα are relative to its discrimination between two receptors R55 and R75.To study the receptor binding sites of TNFα and furthermore to design new TNFα mutants with fewer side effects,the model structures of TNFα receptor R75 (extracellular domain from Cys18 to Phe147) and the complexes of TNFα with the extracellular regions of receptor R55 and R75,have been built by using the homology modeling method based on the known crystal structures of TNFα (1TNF) and R55lymphotoxin complex (1TNR).In the building of R75 model,structural conserved regions are defined dominantly according to the cysteine pattern which is very conserved in the TNFα receptor family.And the models of the complexes are built by the replacement of TNFα Asubunit from lymphotoxin in 1TNR.From these modeling results,the interaction between TNF and receptors are studied.Because the active form of TNFα and its receptors are all trimers,an interactive system comprised of a asymmetric TNFα trimer and a receptor monomer (R55 or R75) is selected to be studied.The crucial structural mechanism and the key residues involved in the discrimination of TNF between the R55 and R75 receptors are defined,which is helpful to the realization of the experiment results,and will guide new mutant designs as well.