Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy
文献类型：期刊论文
| 作者 | Dal Maso, Emma8; Zhu, Yue1,2,4,7; Vi Pham8; Reynolds, Christopher A.6; Deganutti, Giuseppe6; Hick, Caroline A.8; Yang, Dehua1,7 ; Christopoulos, Arthur8; Hay, Debbie L.5; Wang, Ming-Wei1,3,4,7
|
| 刊名 | BIOCHEMICAL PHARMACOLOGY
 |
| 出版日期 | 2018-04 |
| 卷号 | 150页码:212-242 |
| 关键词 | G protein-coupled receptor Calcitonin receptor GPCR structure-function Biased agonism Molecular modelling |
| ISSN号 | 0006-2952 |
| DOI | 10.1016/j.bcp.2018.02.005 |
| 文献子类 | Article |
| 英文摘要 | Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/CAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway-specific effects, and this has implications for the future design of biased agonists of class B GPCRs. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; CRYO-EM STRUCTURE ; CLASS-B GPCRS ; MOLECULAR-DYNAMICS ; SALMON-CALCITONIN ; DIFFERENTIALLY MODULATE ; GLP-1 RECEPTOR ; BIASED AGONISM ; ADRENOMEDULLIN ; FAMILY |
| 资助项目 | National Health and Medical Research Council of Australia (NHMRC)[1061044] ; National Health and Medical Research Council of Australia (NHMRC)[1065410] ; National Health and Medical Research Council of Australia (NHMRC)[1126857] ; NHMRC[1055134] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Chinese Academy of Sciences (CAS)-Novo Nordisk Research Fund[00000000] ; United Kingdom Biotechnology Biological Sciences Research Council[BB/M006883/1] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000431287100021 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279819]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Sexton, Patrick M.; Furness, Sebastian G. B.; Wootten, Denise |
| 作者单位 | 1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 5.Univ Auckland, Sch Biol Sci, 3 Symonds St, Auckland 1142, New Zealand; 6.Univ Essex, Sch Biol Sci, Wivenhoe Pk, Colchester CO4 3SQ, Essex, England; 7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 8.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia; |
| 推荐引用方式 GB/T 7714 | Dal Maso, Emma,Zhu, Yue,Vi Pham,et al. Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy[J]. BIOCHEMICAL PHARMACOLOGY,2018,150:212-242. |
| APA | Dal Maso, Emma.,Zhu, Yue.,Vi Pham.,Reynolds, Christopher A..,Deganutti, Giuseppe.,...&Wootten, Denise.(2018).Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.BIOCHEMICAL PHARMACOLOGY,150,212-242. |
| MLA | Dal Maso, Emma,et al."Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy".BIOCHEMICAL PHARMACOLOGY 150(2018):212-242. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。