The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor

Erik Landin; Silvia Lovera; Gianni de Fabritiis; Sebastien Kelm; Joel Mercier; David McMillan; Richard Sessions; Richard J Taylor; Zara Sands; Lisa Joedicke; Matthew Crump

doi:10.1002/anie.201902852

The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor

Erik Landin, Silvia Lovera, Gianni de Fabritiis, Sebastien Kelm, Joel Mercier, David McMillan, Richard Sessions, Richard J Taylor, Zara Sands, Lisa Joedicke^*, Matthew Crump

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

3 Citations (Scopus)

201 Downloads (Pure)

Abstract

The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.

Original language	English
Pages (from-to)	9399-9403
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	58
Issue number	28
Early online date	16 May 2019
DOIs	https://doi.org/10.1002/anie.201902852
Publication status	Published - 8 Jul 2019

Research Groups and Themes

BrisSynBio
Bristol BioDesign Institute

Keywords

G-protein coupled receptor
NMR spectroscopy
molecular dynamics
conformational flexibility
inactive state
Synthetic biology

Access to Document

10.1002/anie.201902852

Full-text PDF (accepted author manuscript)
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Wiley at https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201902852. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 5.07 MB

Handle.net

Persistent link

Cite this

@article{871c82d0261a4a3b9315c68e730583a3,

title = "The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor",

abstract = "The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.",

keywords = "G-protein coupled receptor, NMR spectroscopy, molecular dynamics, conformational flexibility, inactive state, Synthetic biology",

author = "Erik Landin and Silvia Lovera and {de Fabritiis}, Gianni and Sebastien Kelm and Joel Mercier and David McMillan and Richard Sessions and Taylor, {Richard J} and Zara Sands and Lisa Joedicke and Matthew Crump",

year = "2019",

month = jul,

day = "8",

doi = "10.1002/anie.201902852",

language = "English",

volume = "58",

pages = "9399--9403",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "Wiley-VCH Verlag",

number = "28",

}

TY - JOUR

T1 - The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor

AU - Landin, Erik

AU - Lovera, Silvia

AU - de Fabritiis, Gianni

AU - Kelm, Sebastien

AU - Mercier, Joel

AU - McMillan, David

AU - Sessions, Richard

AU - Taylor, Richard J

AU - Sands, Zara

AU - Joedicke, Lisa

AU - Crump, Matthew

PY - 2019/7/8

Y1 - 2019/7/8

N2 - The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.

AB - The widely expressed G-protein coupled receptors (GPCRs) are versatile signal transducer proteins that are attractive drug targets but structurally challenging to study. GPCRs undergo a number of conformational rearrangements when transitioning from the inactive to the active state but have so far been believed to adopt a fairly conserved inactive conformation. Using 19F NMR spectroscopy and advanced molecular dynamics simulations we describe a novel inactive state of the adenosine 2A receptor which is stabilised by the aminotriazole antagonist Cmpd-1. We demonstrate that the ligand stabilises a unique conformation of helix V and present data on the putative binding mode of the compound involving contacts to the transmembrane bundle as well as the extracellular loop 2.

KW - G-protein coupled receptor

KW - NMR spectroscopy

KW - molecular dynamics

KW - conformational flexibility

KW - inactive state

KW - Synthetic biology

UR - http://www.scopus.com/inward/record.url?scp=85067485670&partnerID=8YFLogxK

U2 - 10.1002/anie.201902852

DO - 10.1002/anie.201902852

M3 - Article (Academic Journal)

C2 - 31095849

AN - SCOPUS:85067485670

SN - 1433-7851

VL - 58

SP - 9399

EP - 9403

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 28

ER -

The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor

Abstract

Research Groups and Themes

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

BrisSynBio: Bristol Centre for Synthetic Biology

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Professor Matthew P Crump

Cite this

The Aminotriazole Antagonist Cmpd-1 Stabilises a Novel Inactive State of the Adenosine 2A Receptor

Abstract

Research Groups and Themes

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

Projects

BrisSynBio: Bristol Centre for Synthetic Biology

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Profiles

Professor Matthew P Crump

Cite this