TY - JOUR
T1 - Full-length human GLP-1 receptor structure without orthosteric ligands
AU - Wu, Fan
AU - Yang, Linlin
AU - Hang, Kaini
AU - Laursen, Mette
AU - Wu, Lijie
AU - Han, Gye Won
AU - Ren, Qiansheng
AU - Roed, Nikolaj Kulahin
AU - Lin, Guangyao
AU - Hanson, Michael A.
AU - Jiang, Hualiang
AU - Wang, Ming Wei
AU - Reedtz-Runge, Steffen
AU - Song, Gaojie
AU - Stevens, Raymond C.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.
AB - Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family.
UR - https://www.scopus.com/pages/publications/85081638914
U2 - 10.1038/s41467-020-14934-5
DO - 10.1038/s41467-020-14934-5
M3 - 文章
C2 - 32152292
AN - SCOPUS:85081638914
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1272
ER -
