Structural mechanism of ligand activation in human calcium-sensing receptor
文献类型：期刊论文
| 作者 | Geng, Yong6,7 ; Mosyak, Lidia7; Kurinov, Igor5; Zuo, Hao7; Sturchler, Emmanuel4; Cheng, Tat Cheung7; Subramanyam, Prakash3; Brown, Alice P.1; Brennan, Sarah C.1; Mun, Hee-chang1
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| 刊名 | ELIFE
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| 出版日期 | 2016-07-19 |
| 卷号 | 5 |
| ISSN号 | 2050-084X |
| DOI | 10.7554/eLife.13662 |
| 文献子类 | Article |
| 英文摘要 | Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca2+ homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca2+ and PO43- ions. Both ions are crucial for structural integrity of the receptor. While Ca2+ ions stabilize the active state, PO43-- ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits. |
| WOS关键词 | METABOTROPIC GLUTAMATE-RECEPTOR ; EXTRACELLULAR CA2+-SENSING RECEPTOR ; NEONATAL SEVERE HYPERPARATHYROIDISM ; FUNCTIONAL GABA(B) RECEPTOR ; HUMAN CA2+ RECEPTOR ; HYPOCALCIURIC HYPERCALCEMIA ; INDUCED REARRANGEMENT ; AMINO-ACIDS ; DOMAIN ; IDENTIFICATION |
| 资助项目 | National Institute of General[R01GM112973] ; American Heart Association[15GRNT25420002] |
| WOS研究方向 | Life Sciences & Biomedicine - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000380848900001 |
| 出版者 | ELIFE SCIENCES PUBLICATIONS LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275951]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Fan, Qing R. |
| 作者单位 | 1.Univ Sydney, Sch Life & Environm Sci, Sydney, NSW 2006, Australia; 2.Columbia Univ, Dept Psychiat, New York, NY USA; 3.Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY USA; 4.Scripps Translat Sci Inst, Dept Mol Therapeut, Jupiter, FL USA; 5.Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY USA; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China; 7.Columbia Univ, Dept Pharmacol, New York, NY 10027 USA; 8.Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA |
| 推荐引用方式 GB/T 7714 | Geng, Yong,Mosyak, Lidia,Kurinov, Igor,et al. Structural mechanism of ligand activation in human calcium-sensing receptor[J]. ELIFE,2016,5. |
| APA | Geng, Yong.,Mosyak, Lidia.,Kurinov, Igor.,Zuo, Hao.,Sturchler, Emmanuel.,...&Fan, Qing R..(2016).Structural mechanism of ligand activation in human calcium-sensing receptor.ELIFE,5. |
| MLA | Geng, Yong,et al."Structural mechanism of ligand activation in human calcium-sensing receptor".ELIFE 5(2016). |
入库方式： OAI收割
来源：上海药物研究所
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