EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural analysis of the dual agonism at GLP-1R and GCGR.
ジャーナル・号・ページ	Proc Natl Acad Sci U S A, Vol. 120, Issue 33, Page e2303696120, Year 2023
掲載日	2023年8月15日
著者	Yang Li / Qingtong Zhou / Antao Dai / Fenghui Zhao / Rulue Chang / Tianlei Ying / Beili Wu / Dehua Yang / Ming-Wei Wang / Zhaotong Cong /
PubMed 要旨	Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They ...Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric G protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.
リンク	Proc Natl Acad Sci U S A / PubMed:37549266 / PubMed Central
手法	EM (単粒子)
解像度	2.46 - 3.4 Å
構造データ	36323 8jip EMDB-36323, PDB-8jip: Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GLP-1R-Gs complex 手法: EM (単粒子) / 解像度: 2.85 Å 36324 8jiq EMDB-36324, PDB-8jiq: Cryo-EM structure of the GLP-1R/GCGR dual agonist Peptide 15-bound human GCGR-Gs complex 手法: EM (単粒子) / 解像度: 3.4 Å 36325 8jir EMDB-36325, PDB-8jir: Cryo-EM structure of the GLP-1R/GCGR dual agonist SAR425899-bound human GLP-1R-Gs complex 手法: EM (単粒子) / 解像度: 2.57 Å 36326 8jis EMDB-36326, PDB-8jis: Cryo-EM structure of the GLP-1R/GCGR dual agonist peptide15-bound human GLP-1R-Gs complex 手法: EM (単粒子) / 解像度: 2.46 Å 36327 8jit EMDB-36327, PDB-8jit: Cryo-EM structure of the GLP-1R/GCGR dual agonist MEDI0382-bound human GCGR-Gs complex 手法: EM (単粒子) / 解像度: 2.91 Å 36328 8jiu EMDB-36328, PDB-8jiu: Cryo-EM structure of the GLP-1R/GCGR dual agonist SAR425899-bound human GCGR-Gs complex 手法: EM (単粒子) / 解像度: 2.76 Å
化合物	ChemComp-D6M: N-hexadecanoyl-L-glutamic acid / N-ヘキサデカノイル-L-グルタミン酸
由来	homo sapiens (ヒト) synthetic construct (人工物) rattus norvegicus (ドブネズミ) bos taurus (ウシ) escherichia coli (大腸菌)
キーワード	STRUCTURAL PROTEIN / G protein-coupled receptor / ligand recognition / receptor activation / unimolecular dual agonist