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Nature. 2019 Aug;572(7767):80-85. doi: 10.1038/s41586-019-1337-6. Epub 2019 Jun 26.

Conformational transitions of a neurotensin receptor 1-Gi1 complex.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
2
Komaba Institute for Science, The University of Tokyo, Tokyo, Japan.
3
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Pathology of Sir Run Run Shaw Hospital, Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, China.
5
Department of Computer Science, Stanford University, Stanford, CA, USA.
6
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
7
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
8
Department of Computer Science, University of Copenhagen, Copenhagen, Denmark.
9
Biophysics Program, Stanford University, Stanford, CA, USA.
10
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kobilka@stanford.edu.
11
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.
12
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. yiorgo@stanford.edu.

Abstract

Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric Gi1 protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR-Gi/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.

PMID:
31243364
DOI:
10.1038/s41586-019-1337-6

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