当前位置: X-MOL 学术Nature › 论文详情
Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure
Nature ( IF 40.137 ) Pub Date : 2017-08-16 , DOI: 10.1038/nature23652
Xiangyu Liu, Seungkirl Ahn, Alem W. Kahsai, Kai-Cheng Meng, Naomi R. Latorraca, Biswaranjan Pani, A. J. Venkatakrishnan, Ali Masoudi, William I. Weis, Ron O. Dror, Xin Chen, Robert J. Lefkowitz, Brian K. Kobilka

G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β2 adrenergic receptor (β2AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.
更新日期:2017-08-16

 

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
分享到
评论: 0
期刊列表
“2017年度学术公众号”入围榜单出炉,敬请投X-MOL一票
南开大学环境科学与工程学院罗义课题组招博士后1名(微生物免疫学、分子生物学和生物信息学)
中科院化学所张德清研究员课题组招聘启事
华中师范大学第一届国际青年学者化学科学论坛
【问答】超薄二维非层状晶体材料在能量存储与转换中有哪些应用?
2017年中科院JCR分区化学大类列表
试剂库存管理
化合物查询
down
wechat
bug