Activation and conformational dynamics of a class B G-protein-coupled glucagon receptor

2016 ◽  
Vol 18 (18) ◽  
pp. 12642-12650 ◽  
Author(s):  
Yang Li ◽  
Jixue Sun ◽  
Dongmei Li ◽  
Jianping Lin
Keyword(s):  
Hydrogen Bonds ◽  
G Protein ◽  
Conformational Dynamics ◽  
Glucagon Receptor ◽  
Class B ◽  
G Protein Coupled

The binding of the agonist glucagon would induce the conformational dynamics and activation of the GCGR. The activation led to the outward movement of helix VII and breaking of two hydrogen bonds.

scholarly journals Interaction of Glucagon G-Protein Coupled Receptor with Known Natural Antidiabetic Compounds: MultiscoringIn SilicoApproach

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
M. H. Baig ◽  
K. Ahmad ◽  
Q. Hasan ◽  
M. K. A. Khan ◽  
N. S. Rao ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
Scoring Function ◽  
Natural Compounds ◽  
G Protein Coupled Receptors ◽  
Binding Potential ◽  
Glucagon Receptor ◽  
Class B ◽  
G Protein Coupled

Glucagon receptor (GCGR) is a secretin-like (class B) family of G-protein coupled receptors (GPCRs) in humans that plays an important role in elevating the glucose concentration in blood and has thus become one of the promising therapeutic targets for treatment of type 2 diabetes mellitus. GCGR based inhibitors for the treatment of type 2 diabetes are either glucagon neutralizers or small molecular antagonists. Management of diabetes without any side effects is still a challenge to the medical system, and the search for a new and effective natural GCGR antagonist is an important area for the treatment of type 2 diabetes. In the present study, a number of natural compounds containing antidiabetic properties were selected from the literature and their binding potential against GCGR was determined using molecular docking and otherin silicoapproaches. Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin. These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from the GOLD andx-score. Further experiments were conducted to identify the atomic level interactions of selected compounds with GCGR.

scholarly journals A combined activation mechanism for the glucagon receptor

2020 ◽  
Vol 117 (27) ◽  
pp. 15414-15422
Author(s):  
Giulio Mattedi ◽  
Silvia Acosta-Gutiérrez ◽  
Timothy Clark ◽  
Francesco Luigi Gervasio
Keyword(s):  
G Protein ◽  
Receptor Agonist ◽  
Structural Data ◽  
Activation Mechanism ◽  
Glucagon Receptor ◽  
Gpcr Activation ◽  
Class B ◽  
G Protein Coupled ◽  
Conformational Free Energy ◽  
Important Drug

We report on a combined activation mechanism for a class B G-protein–coupled receptor (GPCR), the glucagon receptor. By computing the conformational free-energy landscape associated with the activation of the receptor–agonist complex and comparing it with that obtained with the ternary complex (receptor–agonist–G protein) we show that the agonist stabilizes the receptor in a preactivated complex, which is then fully activated upon binding of the G protein. The proposed mechanism contrasts with the generally assumed GPCR activation mechanism, which proceeds through an opening of the intracellular region allosterically elicited by the binding of the agonist. The mechanism found here is consistent with electron cryo-microscopy structural data and might be general for class B GPCRs. It also helps us to understand the mode of action of the numerous allosteric antagonists of this important drug target.

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

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk

Biochemistry ◽  
2018 ◽  
Vol 57 (8) ◽  
pp. 1410-1422 ◽  
Author(s):  
Michael L. Garelja ◽  
Christina A. Walker ◽  
Andrew Siow ◽  
Sung H. Yang ◽  
Paul W.R. Harris ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Activity ◽  
Calcitonin Receptor ◽  
G Protein Coupled Receptor ◽  
Class B ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled

scholarly journals Function-related conformational dynamics of G protein–coupled receptors revealed by NMR

2019 ◽  
Vol 11 (3) ◽  
pp. 409-418 ◽  
Author(s):  
Takumi Ueda ◽  
Yutaka Kofuku ◽  
Junya Okude ◽  
Shunsuke Imai ◽  
Yutaro Shiraishi ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Dynamics ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled
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