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| 1 | A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor显示文摘Glucagon-like peptides(GLP-1 and GLP-2)are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors(GLP-1R and GLP-2R)which are important drug targets for metabolic disorders and Crohn's disease,respectively.Despite great progress in GLP-1 R structure determination,our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive.Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs heterotrimer.To accommodate GLP-2 rather than GLP-1,GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices(TMs)1,5,7 and extracellular loop 1(ECL1).In contrast to GLP-1,the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation.The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2,and the GLP-2 C-terminus closely attaches to ECL1,which is the most protruded among 9 class B G protein-coupled receptors(GPCRs).Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation,especially the middle region.These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics. | Wen Sun Li-Nan Chen Qingtong Zhou Li-Hua Zhao Dehua Yang Huibing Zhang Zhaotong Cong Dan-Dan Shen Fenghui Zhao Fulai Zhou Xiaoqing Cai Yan Chen Yan Zhou Sarina Gadgaard Wijnand JCvan der Velden Suwen Zhao Yi Jiang Mette MRosenkilde HEric Xu Yan Zhang Ming-Wei Wang | 2020 | Cell Research2020，30，12： | 4 |
| 2 | Structural insights into the activation of GLP-1R by a small molecule agonist显示文摘Dear Editor,The glucagon-like peptide-1 receptor(GLP-1R)belongs to class B G protein-coupled receptors(GPCRs).It is a clinically proven target for type 2 diabetes and obesity.1 Several peptidic drugs have been approved including one in pill form,the oral semaglutide.Despite these advances,oral non-peptidic medicines have been pursued across the pharmaceutical industry for improved patient compliance with reduced side effects such as nausea and vomiting.1 The discovery of non-peptidic drugs has been hampered for many years,primarily owing to the difficulty of mimicking the peptide-receptor interactions with small molecule non-peptidic agonists. | Honglei Ma Wei Huang Xiaoxi Wang Lihua Zhao Yi Jiang Feng Liu Wei Guo Xianqiang Sun Wenge Zhong Daopeng Yuan HEric Xu | 2020 | Cell Research2020，30，12： | 1 |
| 3 | Structural basis of humanα7 nicotinic acetylcholine receptor activation显示文摘Dear Editor,Nicotinic acetylcholine receptors(nAChRs)are a class of pentameric ligand-gated ion channels(pLGICs)widely expressed in nervous system.nAChRs function as neurotransmitter receptors that respond to endogenous acetylcholine and choline,modulating neuronal excitability and synaptic communication.The homomericα7 nAChR is among the most abundant subtypes of nAChR in the brain.Dysfunction ofα7 is found to be associated with several neuropsychiatric and neurologic disorders,including schizophrenia and Alzheimer’s disease.1,2 Stimulation ofα7 has been reported to improve attention,cognitive performance,and neuronal resistance to injury.Therefore,agonists and positive allosteric modulators(PAMs)ofα7 have become hot candidates in the drug development for the treatment ofα7-related diseases.3,4 EVP-6124(abbreviated as EVP)is a high-affinityα7-selective agonist.5 PNU-120596(abbreviated as PNU)is the first reportedα7-selective PAM that could increase the peak current of the receptor evoked by agonists and delay channel desensitization.6 Both EVP and PNU are in clinical trials for the treatment of Alzheimer’s disease,schizophrenia,and cognitive impairment.Despite the significance ofα7 in physiology and pharmacology,the mechanisms underlying the activation ofα7 upon agonist and/or PAM binding remain elusive.Little is known about the structural basis of the higher selectivity of EVP and PNU forα7,which would be highly valuable for rational drug development targeting the receptor.Herein,we report the structures of full-length humanα7 in apo,EVP-bound and EVP/PNU-bound states at 3.18,2.85 and 3.02Å,respectively(Fig.1a–c;Supplementary information,Figs.S1–S4 and Table S1). | Yue Zhao Sanling Liu Yingxin Zhou Mengge Zhang Haopeng Chen HEric Xu Demeng Sun Lei Liu Changlin Tian | 2021 | Cell Research2021，31，6： | 0 |
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