Calmodulin interacts with the cytoplasmic tails of the parathyroid hormone 1 receptor and a sub-set of class b G-protein coupled receptors

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.

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Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023301 ◽

2020 ◽

Vol 60 (1) ◽

pp. 89-107 ◽

Cited By ~ 7

Author(s):

Denise Wootten ◽

Laurence J. Miller

Keyword(s):

G Protein ◽

Allosteric Modulation ◽

G Protein Coupled Receptors ◽

Structural Basis ◽

Allosteric Modulators ◽

Class B ◽

Endogenous Proteins ◽

And Function ◽

Agonist Ligands ◽

G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

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Faculty Opinions recommendation of Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727462152.793533650 ◽

2017 ◽

Author(s):

Norma Allewell

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Constitutive Activation ◽

Class B ◽

G Protein Coupled

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Decision letter for "Design and preparation of the class B G protein‐coupled receptors GLP‐1R and GCGR for 19 F‐NMR studies in solution"

10.1111/febs.15686/v1/decision1 ◽

2020 ◽

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Nmr Studies ◽

Class B ◽

G Protein Coupled

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Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies

Journal of The Royal Society Interface ◽

10.1098/rsif.2012.0846 ◽

2013 ◽

Vol 10 (79) ◽

pp. 20120846 ◽

Cited By ~ 33

Author(s):

Shabana Vohra ◽

Bruck Taddese ◽

Alex C. Conner ◽

David R. Poyner ◽

Debbie L. Hay ◽

...

Keyword(s):

G Protein ◽

Calcitonin Gene Related Peptide ◽

G Protein Coupled Receptors ◽

Cgrp Receptor ◽

Conserved Residues ◽

Related Peptide ◽

Class A ◽

Calcitonin Gene ◽

Class B ◽

G Protein Coupled

Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg 2.39 , His 2.43 and Glu 3.46 , which makes a polar lock with T 6.37 . These alignments and models provide useful tools for understanding class B GPCR function.

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