Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics

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	Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics
	Ling, Baoping ; Dong, Lihua ; Zhang, Rui ; Wang, Zhiguo ; Liu, Yongjun ; Liu, Chengbu
	2010-11-01
发表期刊	JOURNAL OF MOLECULAR GRAPHICS & MODELLING ; Ling, BP; Dong, LH; Zhang, R; Wang, ZG; Liu, YJ; Liu, CB.Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics,JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2010,29(3):354-362
摘要	X-linked IAP can bind caspase-9 and inhibit its activity. Mitochondrial protein Smac/DIABLO can also interact with XIAP and relieve the inhibition on caspase-9 to induce apoptosis. A series of artificial Smac mimetics have been used to mimic the Smac N-terminal tetrapeptide AVPI to bind to XIAP-BIR3, but these structural diverse mimetics exhibited distinct binding affinities. To get an insight into the binding nature and optimize the structures, molecular docking and dynamics simulations were used to study the binding of XIAP-BIR3 with three groups of Smac mimetics. The docking results reveal that these Smac mimetics anchored on the surface groove of XIAP-BIR3 and superimposed well with AVPI. The modifications on the seven-membered ring of bicyclic core segment do not strengthen the binding affinity, while a benzyl introduced to the five-membered ring is favorable to the binding. Molecular dynamics simulations on three typical systems show that these complexes are very stable. Hydrogen bonds between the bicyclic core segment and Thr308 play critical roles in maintaining the stability of complex. The binding free energies calculated by MM_PBSA method are consistent with the experimental results. (C) 2010 Elsevier Inc. All rights reserved.; X-linked IAP can bind caspase-9 and inhibit its activity. Mitochondrial protein Smac/DIABLO can also interact with XIAP and relieve the inhibition on caspase-9 to induce apoptosis. A series of artificial Smac mimetics have been used to mimic the Smac N-terminal tetrapeptide AVPI to bind to XIAP-BIR3, but these structural diverse mimetics exhibited distinct binding affinities. To get an insight into the binding nature and optimize the structures, molecular docking and dynamics simulations were used to study the binding of XIAP-BIR3 with three groups of Smac mimetics. The docking results reveal that these Smac mimetics anchored on the surface groove of XIAP-BIR3 and superimposed well with AVPI. The modifications on the seven-membered ring of bicyclic core segment do not strengthen the binding affinity, while a benzyl introduced to the five-membered ring is favorable to the binding. Molecular dynamics simulations on three typical systems show that these complexes are very stable. Hydrogen bonds between the bicyclic core segment and Thr308 play critical roles in maintaining the stability of complex. The binding free energies calculated by MM_PBSA method are consistent with the experimental results. (C) 2010 Elsevier Inc. All rights reserved.
文献类型	期刊论文
条目标识符	http://210.75.249.4/handle/363003/20490
专题	中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	Ling, Baoping,Dong, Lihua,Zhang, Rui,et al. Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics[J]. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, Ling, BP; Dong, LH; Zhang, R; Wang, ZG; Liu, YJ; Liu, CB.Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics,JOURNAL OF MOLECULAR GRAPHICS & MODELLING,2010,29(3):354-362,2010.
APA	Ling, Baoping,Dong, Lihua,Zhang, Rui,Wang, Zhiguo,Liu, Yongjun,&Liu, Chengbu.(2010).Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics.JOURNAL OF MOLECULAR GRAPHICS & MODELLING.
MLA	Ling, Baoping,et al."Theoretical studies on the interactions of XIAP-BIR3 domain with bicyclic and tricyclic core monovalent Smac mimetics".JOURNAL OF MOLECULAR GRAPHICS & MODELLING (2010).