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

doi:10.7503/cjcu20170547

Abstract

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

CLC Number:

O641
Q518

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2018, 39(5): 1026.

Figures/Tables 9

References 27

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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