胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究

doi:10.7503/cjcu20170547

高等学校化学学报 ›› 2018, Vol. 39 ›› Issue (5): 1026.doi: 10.7503/cjcu20170547

胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究

曹洪玉^1,², 金晓军¹, 郭委¹, 余雅娴¹, 史龙飞³, 唐乾^1,², 郑学仿^1,²

1. 大连大学生命科学与技术学院, 2. 辽宁省生物有机化学重点实验室, 大连 116622
3. 齐鲁制药有限公司, 济南 250101

收稿日期:2017-08-10 出版日期:2018-04-18 发布日期:2018-04-18
作者简介:
联系人简介: 郑学仿, 男, 博士, 教授, 博士生导师, 主要从事生物无机化学方面的研究. E-mail: dlxfzheng@126.com ; 曹洪玉, 男, 副教授, 主要从事物理化学方面的研究. E-mail: caohongyu@foxmail.com
基金资助:
国家自然科学基金(批准号: 21571025, 21601025, 21601024)和大连市青年科技之星项目(批准号: 2016-61)资助.

Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations^†

CAO Hongyu^1,^2,^*, JIN Xiaojun¹, GUO Wei¹, YU Yaxian¹, SHI Longfei³, TANG Qian^1,², ZHENG Xuefang^1,^2,^*

1. College of Life Science and Biotechnology, 2. Liaoning Key Laboratory of Bio-Organic Chemistry, Dalian University, Dalian 116622, China
3. Qilu Pharmaceutical, Jinan 250101, China

Received:2017-08-10 Online:2018-04-18 Published:2018-04-18
Contact: CAO Hongyu,ZHENG Xuefang
Supported by:
Supported by the National Natural Science Foundation of China(Nos.21571025, 21601025, 21601024) and the Project of Young Science and Technology Star of Dalian City, China(No.2016-61).

摘要/Abstract

摘要：

采用分子动力学模拟方法研究了胰高血糖素样肽-1(GLP-1)与GLP-1受体(GLP-1R)胞外区域的相互作用. 结果表明, 配体的结合导致受体的构象发生改变, Loop2区域的氨基酸Pro90和Trp91以及C末端的Glu128向配体移动. 根据保守位点突变受体(P73A, V81L, Y88A, P90A和W91A)后所得多肽模拟数据, 发现Loop2区域在突变体中的结构和柔性均发生了明显变化, Trp91和Tyr88的突变将导致配体亲和力丧失. 研究结果证明, P73A突变型受体和野生型受体分别与配体相互作用后, 二者数值差别不大, 因此Pro73不是关键残基; V81L突变体则会导致配体亲和力的丧失. 该结果为GLP-1药物设计提供了重要理论依据.

关键词: 胰高血糖素样肽-1, 保守位点, 分子动力学模拟, 突变体

Abstract:

Binding interactions between the extracellular amino-terminal domain(ECD) of glucagon-like peptide-1(GLP-1) receptor and GLP-1 were studied by molecular dynamics simulations. As shown in calculation results, the binding ligand led to conformational changes of the receptor. Pro90 and Trp91 in Loop2 and Glu128 in the C-terminus moved towards the ligand upon ligand binding. The receptor ECD was mutated in some conserved residues(P73A, V81L, Y88A, P90A and W91A), whose structures and flexibilities have changed violently. Mutations of Trp91 and Tyr88 led to complete loss of binding affinity of the ligand and the effects of those mutations were discussed elaborately. Given all the results, there was no big difference between the interactions related to the receptor ECD^P73A and the wild type, which suggested that Pro73 was not vital for ligand binding, while mutation of V88L might make a complete affinity loss of GLP-1.

Key words: Glucagon-like peptide-1, Conserved site, Molecular dynamics simulation, Mutation

中图分类号:

O641
Q518

TrendMD:

曹洪玉, 金晓军, 郭委, 余雅娴, 史龙飞, 唐乾, 郑学仿. 胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究. 高等学校化学学报, 2018, 39(5): 1026.

CAO Hongyu,JIN Xiaojun,GUO Wei,YU Yaxian,SHI Longfei,TANG Qian,ZHENG Xuefang. Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations^†. Chem. J. Chinese Universities, 2018, 39(5): 1026.

图/表 9

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Donor	Acceptor	Occupancy(%)
Donor	Acceptor	WT	ECD^P73A	ECD^V81L	ECD^Y88A	ECD^P90A	ECD^W91A
Val³⁰-Main	Ser^18*-Side				11.52
Ser³¹-Side	Glu^21*-Side	64.81	42.31	65.99	34.47		78.68
Leu³²-Main	Glu^21*-Side	42.85	38.19	36.57	32.87	42.23	29.47
Lys^26*-Side	Glu¹²⁸-Side	100.84	99.86	92.46	76.60	102.78	89.36
Leu^32*-Side	Glu⁶⁸-Main	13.28	14.74	12.54	11.26	18.22	14.14
Arg¹²¹-Side	Leu^32*-Main			13.06			22.48
Arg¹²¹-Side	Val^33*-Main		10.94	12.56		18.94	25.53
Lys^34*-Side	Glu⁶⁸-Side		41.61		13.76	59.79	10.20
Lys¹¹³-Side	Gly^35*-Main	15.86					12.20
Ser¹¹⁶-Side	Gly^35*-Main			11.90
Lys¹¹³-Side	Gly^35*-Side	22.44	14.26	14.72			25.57
Ser¹¹⁶-Side	Gly^35*-Side	21.32		31.23
Ser¹¹⁷-Main	Gly^35*-Side			19.12
Ser¹¹⁷-Side	Gly^35*-Side			17.98
Arg121-Side	Gly^35*-Main						11.78
Arg121-Side	Gly^35*-Side						30.55

Donor	Acceptor	Occupancy(%)
Donor	Acceptor	WT	ECD^P73A	ECD^V81L	ECD^Y88A	ECD^P90A	ECD^W91A
Val³⁰-Main	Ser^18*-Side				11.52
Ser³¹-Side	Glu^21*-Side	64.81	42.31	65.99	34.47		78.68
Leu³²-Main	Glu^21*-Side	42.85	38.19	36.57	32.87	42.23	29.47
Lys^26*-Side	Glu¹²⁸-Side	100.84	99.86	92.46	76.60	102.78	89.36
Leu^32*-Side	Glu⁶⁸-Main	13.28	14.74	12.54	11.26	18.22	14.14
Arg¹²¹-Side	Leu^32*-Main			13.06			22.48
Arg¹²¹-Side	Val^33*-Main		10.94	12.56		18.94	25.53
Lys^34*-Side	Glu⁶⁸-Side		41.61		13.76	59.79	10.20
Lys¹¹³-Side	Gly^35*-Main	15.86					12.20
Ser¹¹⁶-Side	Gly^35*-Main			11.90
Lys¹¹³-Side	Gly^35*-Side	22.44	14.26	14.72			25.57
Ser¹¹⁶-Side	Gly^35*-Side	21.32		31.23
Ser¹¹⁷-Main	Gly^35*-Side			19.12
Ser¹¹⁷-Side	Gly^35*-Side			17.98
Arg121-Side	Gly^35*-Main						11.78
Arg121-Side	Gly^35*-Side						30.55

胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究

Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations^†

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Residue	Occupancy(%)						Residue	Occupancy(%)
Residue	ECD^P73A		ECD^V81L	ECD^Y88A	ECD^P90A	ECD^W91A	WT	ECD^P73A	ECD^V81L	ECD^Y88A	ECD^P90A	ECD^W91A	WT
S14^*	12	1	16	16	3	12	K26^*	100	99	100	99	98	100
D15^*	9	8	9	10	6	9	E27^*	2	2	2	2	3	2
S17^*	2	1	7	2		5	F28^*	100	100	100	100	100	100
S18^*	93	95	88	92	92	92	I29^*	100	100	100	100	100	100
Y19^*	23	32	29	5	18	18	A30^*	1		1		3	3
E21^*	99	100	100	100	100	100	W31^*	78	20	50	87	81	65
Q23^*	32	26	44	24	14	26	L32^*	100	100	100	100	100	100
A24^*	100	100	100	100	100	100	V33^*	100	100	100	100	100	100
A25^*	100	100	100	100	100	100	K34^*	73	16	99	97	58	41

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胰高血糖素样肽-1受体胞外区域突变体复合物的动力学研究

Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations†

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Investigation on Binding Interactions Between Extracellular Amino-terminal Domain of GLP-1 Receptor Mutations and GLP-1 by Molecular Dynamics Simulations^†