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Structure and dynamics of a constitutively active neurotensin receptor

Journal Article · · Scientific Reports
DOI:https://doi.org/10.1038/srep38564· OSTI ID:1346248
 [1];  [2];  [2];  [3];  [1];  [1];  [2];  [1]
  1. National Inst. of Health (NIH), Rockville, MD (United States). National Inst. of Neurological Disorders and Stroke, Dept. of Health and Human Services
  2. Beckman Research Inst. of the City of Hope, Duarte, CA (United States). Dept. of Molecular Immunology
  3. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Diabetes and Digestive and Kidney Diseases, Lab of Molecular Biology
+ Show Author Affiliations
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. In conclusion, 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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515
OSTI ID:
1346248
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 12, 2016 Vol. 6; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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In vivo assembly and large-scale purification of a GPCR - Gα fusion with Gβγ, and characterization of the active complex journal January 2019
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A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations journal January 2020
New approaches towards the understanding of integral membrane proteins: A structural perspective on G protein-coupled receptors: Structural Perspective on G Protein-Coupled Receptors journal June 2017
Structures of Non-rhodopsin GPCRs Elucidated Through X-Ray Crystallography book January 2017
A benchmark study of loop modeling methods applied to G protein-coupled receptors journal May 2019
A3 adenosine receptor activation mechanisms: molecular dynamics analysis of inactive, active, and fully active states journal November 2019
A complex structure of arrestin-2 bound to a G protein-coupled receptor journal November 2019
Conformational transitions of a neurotensin receptor 1–Gi1 complex journal June 2019
Effect of thermostable mutations on the neurotensin receptor 1 (NTSR 1 ) activation state journal February 2019
A complex structure of arrestin-2 bound to a G protein-coupled receptor journal October 2019
G Protein Preassembly Rescues Efficacy of W 6.48 Toggle Mutations in Neuropeptide Y 2 Receptor journal February 2018
Gonadotropin-Releasing Hormone (GnRH) Receptor Structure and GnRH Binding journal October 2017
In vivo assembly and large-scale purification of a GPCR - Gα fusion with Gβγ, and characterization of the active complex text January 2019

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