Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.
Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes.
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胰高血糖素样肽 1 及其 B 类 G 蛋白偶联受体：通往治疗成功的长征。
DOI：
10.1124/pr.115.011395
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发表时间：
2016-10
影响因子：
21.1
通讯作者：
Wang MW
中科院分区：
文献类型：
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作者：
Graaf Cd;Donnelly D;Wootten D;Lau J;Sexton PM;Miller LJ;Ahn JM;Liao J;Fletcher MM;Yang D;Brown AJ;Zhou C;Deng J;Wang MW
胰高血糖素样肽（GLP）-1受体（GLP-1 R）是一种B类G蛋白偶联受体（GPCR），介导GLP-1的作用，GLP-1是一种由人体三种主要组织分泌的肽激素，即远端肠的肠内分泌L细胞、胰腺中的α细胞和中枢神经系统，在2型糖尿病和肥胖症的治疗中发挥重要作用。包括葡萄糖稳态和胃运动和食物摄取的调节。GLP-1的肽类似物已成功开发，具有增强的生物利用度和药理活性。对截短、嵌合和突变肽和GLP-1 R变体以及配体结合的胞外结构域晶体结构和B类GPCR 7-螺旋跨膜结构域的第一个三维结构进行的生理和生化研究为GLP-1与其同源受体的双结构域结合机制提供了基础。尽管在发现治疗上可行的非肽类GLP-1 R激动剂方面的努力受到阻碍，但小分子调节剂为肽类似物提供了补充化学工具，以研究GLP-1 R的配体导向的偏倚细胞信号传导。不同GLP-1类似物和同源受体的综合药理学和结构信息为GLP-1 R配体选择性和功能活性的分子决定因素提供了新的见解，从而为设计和开发更有效的代谢疾病治疗药物提供了新的机会。
The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.
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影响因子：
--
作者：
Beinborn, M;Worrall, CI;Kopin, AS
通讯作者：
Kopin, AS
影响因子：
11.4
作者：
Belin, D;Bost, S;Strub, K
通讯作者：
Strub, K
影响因子：
4.8
作者：
Ban, Kiwon;Kim, Kyoung-Han;Husain, Mansoor
通讯作者：
Husain, Mansoor
DOI：
10.1073/pnas.84.16.5783
发表时间：
1987-08-01
影响因子：
11.1
作者：
AUDIGIER, Y;FRIEDLANDER, M;BLOBEL, G
通讯作者：
BLOBEL, G
DOI：
10.1038/nrendo.2011.77
发表时间：
2011-06-07
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
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