scholarly journals Modeling the possible conformations of the extracellular loops in G-protein-coupled receptors

2010 ◽  
Vol 78 (2) ◽  
pp. 271-285 ◽  
Author(s):  
Gregory V. Nikiforovich ◽  
Christina M. Taylor ◽  
Garland R. Marshall ◽  
Thomas J. Baranski
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Extracellular Loops ◽  
G Protein Coupled

Enzymatic recycling of ascorbic acid from dehydroascorbic acid by glutathione-like peptides in the extracellular loops of aminergic G-protein coupled receptors

2016 ◽  
Vol 29 (7) ◽  
pp. 296-302 ◽  
Author(s):  
Robert Root-Bernstein ◽  
Jenna Fewins ◽  
Tyler Rhinesmith ◽  
Ariana Koch ◽  
Patrick F. Dillon
Keyword(s):  
Ascorbic Acid ◽  
G Protein ◽  
Dehydroascorbic Acid ◽  
G Protein Coupled Receptors ◽  
Extracellular Loops ◽  
G Protein Coupled

Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors

2007 ◽  
Vol 35 (4) ◽  
pp. 717-720 ◽  
Author(s):  
M. Wheatley ◽  
J. Simms ◽  
S.R. Hawtin ◽  
V.J. Wesley ◽  
D. Wootten ◽  
...  
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Tertiary Structure ◽  
Large Family ◽  
Peptide Hormone ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Ligand Selectivity ◽  
Extracellular Loops ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V1aR (V1a vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg8]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V1aR, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

scholarly journals RosettaGPCR: Multiple Template Homology Modeling of GPCRs with Rosetta

2019 ◽  
Author(s):  
Brian Joseph Bender ◽  
Brennica Marlow ◽  
Jens Meiler
Keyword(s):  
Protein Structure ◽  
Drug Development ◽  
Homology Modeling ◽  
Computational Modeling ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Extracellular Loops ◽  
Model Database ◽  
G Protein Coupled ◽  
Multiple Template

AbstractG-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies. However, to date, only about 10% of druggable GPCRs have had their structures characterized at atomic resolution. Further, because of the flexibility of GPCRs, alternative conformations remain to be modeled, even after an experimental structure is available. Thus, computational modeling of GPCRs is a crucial component for understanding biological function and to aid development of new therapeutics. Previous single- and multi-template homology modeling protocols in Rosetta often generated non-native-like conformations of transmembrane α-helices and/or extracellular loops. Here we present a new Rosetta protocol for modeling GPCRs that is improved in two critical ways: Firstly, it uses a blended sequence- and structure-based alignment that now accounts for structure conservation in extracellular loops. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target GPCR can be used expanding the conformational space sampled in a meaningful way. This new method allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at www.rosettagpcr.org.Author SummaryStructure-based drug discovery is among the new technologies driving the development of next generation therapeutics. Inherent to this process is the availability of a protein structure for virtual screening. The most heavily drugged protein family, G-protein coupled receptors (GPCRs), however suffers from a lack of experimental structures that could hinder drug development. Technical challenges prevent the determination of every protein structure, so we turn to computational modeling to predict the structures of the remaining proteins. Again, traditional techniques fail due to the high divergence of this family. Here, we build on available methods specifically for the challenge of modeling GPCRs. This new method outperforms other methods and allows for the ability to accurately model nearly 90% of the entire GPCR family. We therefore generate a model database of all GPCRs (www.rosettagpcr.org) for use in future drug development.

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