scholarly journals Mapping the Ligand-Binding Site on a G Protein-Coupled Receptor (GPCR) Using Genetically Encoded Photocrosslinkers

Biochemistry ◽  
2011 ◽  
Vol 50 (17) ◽  
pp. 3411-3413 ◽  
Author(s):  
Amy Grunbeck ◽  
Thomas Huber ◽  
Pallavi Sachdev ◽  
Thomas P. Sakmar
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Ligand Binding Site ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Simulations of a G protein-coupled receptor homology model predict dynamic features and a ligand binding site

FEBS Letters ◽  
2008 ◽  
Vol 582 (23-24) ◽  
pp. 3335-3342 ◽  
Author(s):  
Steffen Wolf ◽  
Marcus Böckmann ◽  
Udo Höweler ◽  
Jürgen Schlitter ◽  
Klaus Gerwert
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Homology Model ◽  
Ligand Binding Site ◽  
Dynamic Features ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

2015 ◽  
Vol 48 (4) ◽  
pp. 479-487 ◽  
Author(s):  
Kalli Kappel ◽  
Yinglong Miao ◽  
J. Andrew McCammon
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Partial Agonist ◽  
Md Simulations ◽  
G Protein Coupled Receptor ◽  
Accelerated Molecular Dynamics ◽  
Dynamics Simulations ◽  
G Protein Coupled

AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

scholarly journals Exploring a new ligand binding site of G protein-coupled receptors

2018 ◽  
Vol 9 (31) ◽  
pp. 6480-6489 ◽  
Author(s):  
H. C. Stephen Chan ◽  
Jingjing Wang ◽  
Krzysztof Palczewski ◽  
Slawomir Filipek ◽  
Horst Vogel ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Md Simulations ◽  
Binding Pocket ◽  
G Protein Coupled Receptors ◽  
Ligand Binding Site ◽  
Endogenous Ligand ◽  
G Protein Coupled

A new binding pocket of the endogenous ligand has been discovered by MD simulations.

scholarly journals Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Oliver Fleetwood ◽  
Jens Carlsson ◽  
Lucie Delemotte
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Conformational Ensemble ◽  
G Protein Coupled Receptor ◽  
Dynamics Simulations ◽  
Data Driven Modeling ◽  
G Protein Coupled

Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β2 adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics simulations. These reveal shifts toward active-like states at the Gprotein-binding site for receptors bound to partial and full agonists, and that the ligands modulate the conformational ensemble of the receptor by tuning protein microswitches. We indeed find an excellent correlation between the conformation of the microswitches close to the ligand binding site and in the transmembrane region and experimentally reported cyclic adenosine monophosphate signaling responses. Dimensionality reduction further reveals the similarity between the unique conformational states induced by different ligands, and examining the output of classifiers highlights two distant hotspots governing agonism on transmembrane helices 5 and 7.

Mechanochemical Activation of Class-B G-Protein-Coupled Receptor upon Peptide–Ligand Binding

Nano Letters ◽  
2020 ◽  
Vol 20 (7) ◽  
pp. 5575-5582 ◽  
Author(s):  
Cristina Lo Giudice ◽  
Haonan Zhang ◽  
Beili Wu ◽  
David Alsteens
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Mechanochemical Activation ◽  
Peptide Ligand ◽  
G Protein Coupled Receptor ◽  
Class B ◽  
G Protein Coupled

scholarly journals A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity

2020 ◽  
Vol 13 (617) ◽  
pp. eaaw5885 ◽  
Author(s):  
Marta Sanchez-Soto ◽  
Ravi Kumar Verma ◽  
Blair K. A. Willette ◽  
Elizabeth C. Gonye ◽  
Annah M. Moore ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
G Protein ◽  
Structural Basis ◽  
Protein Signaling ◽  
Ligand Binding Site ◽  
Intracellular Loop ◽  
Gpcr Signaling ◽  
Biased Signaling ◽  
Dynamics Simulations

Signaling bias is the propensity for some agonists to preferentially stimulate G protein–coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein–biased agonist of the D2 dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with β-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired β-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the β2-adrenergic receptor (β2R) to build β2R-WT and β2R-Y1995.38A models in complex with the full β2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in β2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in β2R-Y1995.38A, which is predicted to affect its interactions with β-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.

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