A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor
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A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor. / Sun, Wen; Chen, Li-Nan; Zhou, Qingtong; Zhao, Li-Hua; Yang, Dehua; Zhang, Huibing; Cong, Zhaotong; Shen, Dan-Dan; Zhao, Fenghui; Zhou, Fulai; Cai, Xiaoqing; Chen, Yan; Zhou, Yan; Gadgaard, Sarina; van der Velden, Wijnand J. C.; Zhao, Suwen; Jiang, Yi; Rosenkilde, Mette M.; Xu, H. Eric; Zhang, Yan; Wang, Ming-Wei.
I: Cell Research, Bind 30, Nr. 12, 2020, s. 1098-1108.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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TY - JOUR
T1 - A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor
AU - Sun, Wen
AU - Chen, Li-Nan
AU - Zhou, Qingtong
AU - Zhao, Li-Hua
AU - Yang, Dehua
AU - Zhang, Huibing
AU - Cong, Zhaotong
AU - Shen, Dan-Dan
AU - Zhao, Fenghui
AU - Zhou, Fulai
AU - Cai, Xiaoqing
AU - Chen, Yan
AU - Zhou, Yan
AU - Gadgaard, Sarina
AU - van der Velden, Wijnand J. C.
AU - Zhao, Suwen
AU - Jiang, Yi
AU - Rosenkilde, Mette M.
AU - Xu, H. Eric
AU - Zhang, Yan
AU - Wang, Ming-Wei
PY - 2020
Y1 - 2020
N2 - 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-1R 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 G(s) 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.
AB - 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-1R 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 G(s) 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.
KW - CRYO-EM STRUCTURE
KW - PROTEIN-COUPLED RECEPTOR
KW - GLP-1 RECEPTOR
KW - STRUCTURAL BASIS
KW - IMMUNOHISTOCHEMICAL DETERMINATION
KW - CRYSTAL-STRUCTURE
KW - ACTIVATION
KW - COMPLEX
KW - BINDING
KW - DOMAIN
U2 - 10.1038/s41422-020-00442-0
DO - 10.1038/s41422-020-00442-0
M3 - Journal article
C2 - 33239759
VL - 30
SP - 1098
EP - 1108
JO - Cell Research
JF - Cell Research
SN - 1001-0602
IS - 12
ER -
ID: 257024541