scholarly journals Imaging G protein–coupled receptors while quantifying their ligand-binding free-energy landscape

2015 ◽  
Vol 12 (9) ◽  
pp. 845-851 ◽  
Author(s):  
David Alsteens ◽  
Moritz Pfreundschuh ◽  
Cheng Zhang ◽  
Patrizia M Spoerri ◽  
Shaun R Coughlin ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
G Protein Coupled

scholarly journals Ligand-Induced Modulation of the Free-Energy Landscape of G Protein-Coupled Receptors Explored by Adaptive Biasing Techniques

2011 ◽  
Vol 7 (10) ◽  
pp. e1002193 ◽  
Author(s):  
Davide Provasi ◽  
Marta Camacho Artacho ◽  
Ana Negri ◽  
Juan Carlos Mobarec ◽  
Marta Filizola
Keyword(s):  
Free Energy ◽  
G Protein ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
Adaptive Biasing ◽  
G Protein Coupled

scholarly journals Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243313
Author(s):  
Brandon L. Peters ◽  
Jinxia Deng ◽  
Andrew L. Ferguson
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Intracellular Signaling ◽  
Serotonin Receptor ◽  
Energy Landscape ◽  
Free Energy Calculations ◽  
Free Energy Landscape ◽  
Functional Selectivity ◽  
G Protein Coupled

G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.

The Perturbed Free Energy Landscape: Linking Ligand Binding to Biomolecular Folding

ChemBioChem ◽  
2020 ◽  
Author(s):  
fareed aboul-ela ◽  
Abdallah S Abdelsatter ◽  
Youssef Mansour
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Landscape ◽  
Free Energy Landscape

scholarly journals Free-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism

2019 ◽  
Vol 32 (7) ◽  
pp. 297-308 ◽  
Author(s):  
Junichi Higo ◽  
Kota Kasahara ◽  
Mitsuhito Wada ◽  
Bhaskar Dasgupta ◽  
Narutoshi Kamiya ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Binding Pocket ◽  
Free Energy Landscape ◽  
Type B ◽  
Endothelin 1 ◽  
Reaction Coordinates ◽  
Explicit Solvent ◽  
Virtual System ◽  
G Protein Coupled

Abstract The free-energy landscape of interaction between a medium-sized peptide, endothelin 1 (ET1), and its receptor, human endothelin type B receptor (hETB), was computed using multidimensional virtual-system coupled molecular dynamics, which controls the system’s motions by introducing multiple reaction coordinates. The hETB embedded in lipid bilayer was immersed in explicit solvent. All molecules were expressed as all-atom models. The resultant free-energy landscape had five ranges with decreasing ET1–hETB distance: completely dissociative, outside-gate, gate, binding pocket, and genuine-bound ranges. In the completely dissociative range, no ET1–hETB interaction appeared. In the outside-gate range, an ET1–hETB attractive interaction was the fly-casting mechanism. In the gate range, the ET1 orientational variety decreased rapidly. In the binding pocket range, ET1 was in a narrow pathway with a steep free-energy slope. In the genuine-bound range, ET1 was in a stable free-energy basin. A G-protein-coupled receptor (GPCR) might capture its ligand from a distant place.

Multiparametric Homogeneous Method for Identification of Ligand Binding to G Protein-Coupled Receptors: Receptor–Ligand Binding and β-Arrestin Assay

2013 ◽  
Vol 85 (4) ◽  
pp. 2276-2281 ◽  
Author(s):  
Kari Kopra ◽  
Markus Kainulainen ◽  
Piia Mikkonen ◽  
Anita Rozwandowicz-Jansen ◽  
Pekka Hänninen ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Receptor Ligand ◽  
Homogeneous Method ◽  
G Protein Coupled

Family Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors

2007 ◽  
Vol 35 (4) ◽  
pp. 707-708 ◽  
Author(s):  
D.R. Poyner ◽  
M. Wheatley
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Present Article ◽  
G Protein Coupled Receptors ◽  
Society Meeting ◽  
Family Resemblances ◽  
G Protein Coupled ◽  
Compare And Contrast ◽  
Present Meeting

In April 2007, the Biochemical Society held a meeting to compare and contrast ligand binding and activation of Family A and B GPCRs (G-protein-coupled receptors). Being the largest class, Family A GPCRs usually receive the most attention, although a previous Biochemical Society meeting has focused on Family B GPCRs. The aim of the present meeting was to bring researchers of both families together in order to identify commonalities between the two. The present article introduces the proceedings of the meeting, briefly commenting on the focus of each of the following articles.

scholarly journals Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation

2018 ◽  
Author(s):  
Ashley R. Vidad ◽  
Stephen Macaspac ◽  
Ho-Leung Ng
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Binding Sites ◽  
G Protein Coupled Receptors ◽  
Sequence Conservation ◽  
Surface Geometry ◽  
A2a Adenosine Receptors ◽  
Ligand Binding Sites ◽  
G Protein Coupled ◽  
Homology Models

AbstractG-protein coupled receptors (GPCRs) are the largest protein family of drug targets. Detailed mechanisms of binding are unknown for many important GPCR-ligand pairs due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our new method, ConDock, for predicting ligand binding sites in GPCRs using combined information from surface conservation and docking starting from crystal structures or homology models. We demonstrate the effectiveness of ConDock on well-characterized GPCRs such as the β2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDock successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDock to predict ligand binding sites on a structurally uncharacterized GPCR, GPER. GPER is the G-protein coupled estrogen receptor, with four known ligands: estradiol, G1, G15, and tamoxifen. ConDock predicts that all four ligands bind to the same location on GPER, centered on L119, H307, and N310; this site is deeper in the receptor cleft than predicted by previous studies. We compare the sites predicted by ConDock and traditional methods that utilize information from surface geometry, surface conservation, and ligand chemical interactions. Incorporating sequence conservation information in ConDock overcomes errors introduced from physics-based scoring functions and homology modeling.

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