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Structure and dynamics of a constitutively active neurotensin receptor

Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive...

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Autores principales: Krumm, Brian E., Lee, Sangbae, Bhattacharya, Supriyo, Botos, Istvan, White, Courtney F., Du, Haijuan, Vaidehi, Nagarajan, Grisshammer, Reinhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141500/
https://www.ncbi.nlm.nih.gov/pubmed/27924846
http://dx.doi.org/10.1038/srep38564
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author Krumm, Brian E.
Lee, Sangbae
Bhattacharya, Supriyo
Botos, Istvan
White, Courtney F.
Du, Haijuan
Vaidehi, Nagarajan
Grisshammer, Reinhard
author_facet Krumm, Brian E.
Lee, Sangbae
Bhattacharya, Supriyo
Botos, Istvan
White, Courtney F.
Du, Haijuan
Vaidehi, Nagarajan
Grisshammer, Reinhard
author_sort Krumm, Brian E.
collection PubMed
description Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive activity, we report here the 3.3 Å crystal structure of a constitutively active, agonist-bound neurotensin receptor (NTSR1) and molecular dynamics simulations of agonist-occupied and ligand-free receptor. Comparison with the structure of a NTSR1 variant that has little constitutive activity reveals uncoupling of the ligand-binding domain from conserved connector residues, that effect conformational changes during GPCR activation. Furthermore, molecular dynamics simulations show strong contacts between connector residue side chains and increased flexibility at the intracellular receptor face as features that coincide with robust signalling in cells. The loss of correlation between the binding pocket and conserved connector residues, combined with altered receptor dynamics, possibly explains the reduced neurotensin efficacy in the constitutively active NTSR1 and a facilitated initial engagement with G protein in the absence of agonist.
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spelling pubmed-51415002016-12-16 Structure and dynamics of a constitutively active neurotensin receptor Krumm, Brian E. Lee, Sangbae Bhattacharya, Supriyo Botos, Istvan White, Courtney F. Du, Haijuan Vaidehi, Nagarajan Grisshammer, Reinhard Sci Rep Article Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive activity, we report here the 3.3 Å crystal structure of a constitutively active, agonist-bound neurotensin receptor (NTSR1) and molecular dynamics simulations of agonist-occupied and ligand-free receptor. Comparison with the structure of a NTSR1 variant that has little constitutive activity reveals uncoupling of the ligand-binding domain from conserved connector residues, that effect conformational changes during GPCR activation. Furthermore, molecular dynamics simulations show strong contacts between connector residue side chains and increased flexibility at the intracellular receptor face as features that coincide with robust signalling in cells. The loss of correlation between the binding pocket and conserved connector residues, combined with altered receptor dynamics, possibly explains the reduced neurotensin efficacy in the constitutively active NTSR1 and a facilitated initial engagement with G protein in the absence of agonist. Nature Publishing Group 2016-12-07 /pmc/articles/PMC5141500/ /pubmed/27924846 http://dx.doi.org/10.1038/srep38564 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Krumm, Brian E.
Lee, Sangbae
Bhattacharya, Supriyo
Botos, Istvan
White, Courtney F.
Du, Haijuan
Vaidehi, Nagarajan
Grisshammer, Reinhard
Structure and dynamics of a constitutively active neurotensin receptor
title Structure and dynamics of a constitutively active neurotensin receptor
title_full Structure and dynamics of a constitutively active neurotensin receptor
title_fullStr Structure and dynamics of a constitutively active neurotensin receptor
title_full_unstemmed Structure and dynamics of a constitutively active neurotensin receptor
title_short Structure and dynamics of a constitutively active neurotensin receptor
title_sort structure and dynamics of a constitutively active neurotensin receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141500/
https://www.ncbi.nlm.nih.gov/pubmed/27924846
http://dx.doi.org/10.1038/srep38564
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