Differential Structural Properties of GLP-1 and Exendin-4 Determine Their Relative Affinity for the GLP-1 Receptor N-Terminal Extracellular Domain

化学 配体(生物化学) 圆二色性 胰高血糖素样肽1受体 受体 跨膜结构域 生物物理学 立体化学 生物化学 生物 兴奋剂
作者
Steffen Runge,Susann Schimmer,Jan Oschmann,Christine Bruun Schiødt,Sanne Möller Knudsen,Claus Jeppesen,Kjeld Madsen,Jesper Lau,Henning Thøgersen,Rainer Rudolph
出处
期刊:Biochemistry [American Chemical Society]
卷期号:46 (19): 5830-5840 被引量:87
标识
DOI:10.1021/bi062309m
摘要

Glucagon-like peptide-1 (GLP-1) and exendin-4 (Ex4) are homologous peptides with established potential for treatment of type 2 diabetes. They bind and activate the pancreatic GLP-1 receptor (GLP-1R) with similar affinity and potency and thereby promote insulin secretion in a glucose-dependent manner. GLP-1R belongs to family B of the seven transmembrane G-protein coupled receptors. The N-terminal extracellular domain (nGLP-1R) is a ligand binding domain with differential affinity for Ex4 and GLP-1: low affinity for GLP-1 and high affinity for exendin-4. The superior affinity of nGLP-1R for Ex4 was previously explained by an additional interaction between nGLP-1R and the C-terminal Trp-cage of Ex4. In this study we have combined biophysical and pharmacological approaches thus relating structural properties of the ligands in solution to their relative binding affinity for nGLP-1R. We used both a tracer competition assay and ligand-induced thermal stabilization of nGLP-1R to measure the relative affinity of full length, truncated, and chimeric ligands for soluble refolded nGLP-1R. The ligands in solution and the conformational consequences of ligand binding to nGLP-1R were characterized by circular dichroism and fluorescence spectroscopy. We found a correlation between the helical content of the free ligands and their relative binding affinity for nGLP-1R, supporting the hypothesis that the ligands are helical at least in the segment that binds to nGLP-1R. The Trp-cage of Ex4 was not necessary to maintain a superior helicity of Ex4 compared to GLP-1. The results suggest that the differential affinity of nGLP-1R is explained almost entirely by divergent residues in the central part of the ligands: Leu10-Gly30 of Ex4 and Val16-Arg36 of GLP-1. In view of our results it appears that the Trp-cage plays only a minor role for the interaction between Ex4 and nGLP-1R and for the differential affinity of nGLP-1R for GLP-1 and Ex4.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
量子星尘发布了新的文献求助10
1秒前
dou完成签到 ,获得积分10
1秒前
小小发布了新的文献求助10
2秒前
柔弱的千秋完成签到,获得积分10
3秒前
4秒前
5秒前
Ava应助上官靖采纳,获得10
7秒前
7秒前
8秒前
脑洞疼应助Hexagram采纳,获得10
8秒前
9秒前
JINYUBAO发布了新的文献求助10
9秒前
zdx1022完成签到,获得积分10
9秒前
小小完成签到,获得积分20
9秒前
10秒前
11秒前
B哥发布了新的文献求助10
11秒前
阿米尔发布了新的文献求助10
11秒前
susu完成签到,获得积分10
11秒前
12秒前
13秒前
13秒前
14秒前
14秒前
JINYUBAO完成签到,获得积分10
15秒前
有魅力的愚志完成签到,获得积分20
16秒前
JamesPei应助重要问筠采纳,获得10
16秒前
机灵白桃发布了新的文献求助10
16秒前
17秒前
李健应助小小采纳,获得10
17秒前
读书的时候完成签到,获得积分10
17秒前
han发布了新的文献求助10
18秒前
gww发布了新的文献求助10
18秒前
19秒前
谯殿艺发布了新的文献求助10
20秒前
TOURIN平行完成签到,获得积分10
20秒前
大模型应助鱼鱼片片采纳,获得10
21秒前
科研通AI2S应助高兴采文采纳,获得10
22秒前
大杨发布了新的文献求助10
22秒前
高分求助中
Picture Books with Same-sex Parented Families: Unintentional Censorship 1000
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 310
The Moiseyev Dance Company Tours America: "Wholesome" Comfort during a Cold War 300
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3979916
求助须知:如何正确求助?哪些是违规求助? 3524003
关于积分的说明 11219349
捐赠科研通 3261424
什么是DOI,文献DOI怎么找? 1800654
邀请新用户注册赠送积分活动 879239
科研通“疑难数据库(出版商)”最低求助积分说明 807214