Conformational transitions of a neurotensin receptor 1–Gi1 complex

Hideaki E. Kato; Yan Zhang; Hongli Hu; Carl Mikael Suomivuori; Francois Marie Ngako Kadji; Junken Aoki; Kaavya Krishna Kumar; Rasmus Fonseca; Daniel Hilger; Weijiao Huang; Naomi R. Latorraca; Asuka Inoue; Ron O. Dror; Brian K. Kobilka; Georgios Skiniotis

doi:10.1038/s41586-019-1337-6

Conformational transitions of a neurotensin receptor 1–G_i1 complex

Hideaki E. Kato, Yan Zhang, Hongli Hu, Carl Mikael Suomivuori, Francois Marie Ngako Kadji, Junken Aoki, Kaavya Krishna Kumar, Rasmus Fonseca, Daniel Hilger, Weijiao Huang, Naomi R. Latorraca, Asuka Inoue, Ron O. Dror, Brian K. Kobilka^*, Georgios Skiniotis

^*Corresponding author for this work

Department of Computer Science

61 Citations (Scopus)

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 G_i1 protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR–G_i/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.

Original language	English
Journal	Nature
Volume	572
Issue number	7767
Pages (from-to)	80-85
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-019-1337-6
Publication status	Published - 2019

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title = "Conformational transitions of a neurotensin receptor 1–Gi1 complex",

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 {\AA}. 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.",

author = "Kato, {Hideaki E.} and Yan Zhang and Hongli Hu and Suomivuori, {Carl Mikael} and Kadji, {Francois Marie Ngako} and Junken Aoki and {Krishna Kumar}, Kaavya and Rasmus Fonseca and Daniel Hilger and Weijiao Huang and Latorraca, {Naomi R.} and Asuka Inoue and Dror, {Ron O.} and Kobilka, {Brian K.} and Georgios Skiniotis",

year = "2019",

doi = "10.1038/s41586-019-1337-6",

language = "English",

volume = "572",

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T1 - Conformational transitions of a neurotensin receptor 1–Gi1 complex

AU - Kato, Hideaki E.

AU - Zhang, Yan

AU - Hu, Hongli

AU - Suomivuori, Carl Mikael

AU - Kadji, Francois Marie Ngako

AU - Aoki, Junken

AU - Krishna Kumar, Kaavya

AU - Fonseca, Rasmus

AU - Hilger, Daniel

AU - Huang, Weijiao

AU - Latorraca, Naomi R.

AU - Inoue, Asuka

AU - Dror, Ron O.

AU - Kobilka, Brian K.

AU - Skiniotis, Georgios

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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SN - 0028-0836

VL - 572

SP - 80

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JO - Nature

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IS - 7767

ER -

Conformational transitions of a neurotensin receptor 1–G_i1 complex

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