Understanding Peptide Binding in Class A G Protein-Coupled Receptors

Tikhonova, Irina G.; Gigoux, Véronique; Fourmy, Daniel

doi:10.1124/mol.119.115915

Cited by 26 publications

(39 citation statements)

References 114 publications

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“…As with the biological role and target tissue, the cognate CCRFamide receptor has yet to be elucidated. Although most regulatory peptides and neuromodulators signal through class A G protein-coupled receptors (GPCRs) (Tikhonova et al, 2019), disulfide-bridged peptides like CCRFamide frequently act on other signaling systems such as insulin-like peptides and prothoracicotropic hormone (PTTH) with tyrosine kinases (Nässel and Zandawala, 2019), eclosion hormone with a guanylate cyclase (Nässel and Zandawala, 2019), or, as proposed for the agatoxin-like peptides, with ion channels (Sturm et al, 2016). Thus, specific identification of the CCRFamide receptor is potentially complicated by the breadth of potential molecular targets.…”

Section: Discussionmentioning

confidence: 99%

Cloning of the first cDNA encoding a putative CCRFamide precursor: identification of the brain, eyestalk ganglia, and cardiac ganglion as sites of CCRFamide expression in the American lobster, Homarus americanus

et al. 2020

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Over the past decade, many new peptide families have been identified via in silico analyses of genomic and transcriptomic datasets. While various molecular and biochemical methods have confirmed the existence of some of these new groups, others remain in silico discoveries of computationally assembled sequences only. An example of the latter are the CCRFamides, named for the predicted presence of two pairs of disulfide bonded cysteine residues and an amidated arginine-phenylalanine carboxyl-terminus in family members, which have been identified from annelid, molluscan, and arthropod genomes/transcriptomes, but for which no precursor proteinencoding cDNAs have been cloned. Using routine transcriptome mining methods, we identified four Homarus americanus (American lobster) CCRFamide transcripts that share high sequence identity across the predicted open reading frames but more limited conservation in their 5' terminal ends, suggesting the Homarus gene undergoes alternative splicing. RT-PCR profiling using primers designed to amplify an internal fragment common to all of the transcripts revealed expression in the supraoesophageal ganglion (brain), eyestalk ganglia, and cardiac ganglion. Variant specific profiling revealed a similar profile for variant 1, eyestalk ganglia specific expression of variant 2, and an absence of variant 3 expression in the cDNAs examined. The broad distribution of CCRFamide transcript expression in the H. americanus nervous system suggests a *

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Section: Discussionmentioning

confidence: 99%

Cloning of the first cDNA encoding a putative CCRFamide precursor: identification of the brain, eyestalk ganglia, and cardiac ganglion as sites of CCRFamide expression in the American lobster, Homarus americanus

et al. 2020

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show abstract

“…For preparation of the GPCR dataset used in this study, we examined all crystal structures of receptor–peptide and receptor–peptidomimetic complexes from the largest Class A of GPCRs [ 24 ]. From the set of nine identified crystal structures, two cases (PDB ID: 4RWD and 5VBL) were rejected due to the content of nonstandard amino acid peptide residues that have no similar counterparts among 20 natural amino acids.…”

Section: Methodsmentioning

confidence: 99%

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Badaczewska-Dawid¹,

Kmiecik²,

Koliński³

2020

Briefings in Bioinformatics

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The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein–peptide complex structures and model scoring. We evaluated the proposed protocol on the set of seven different GPCR–peptide complexes (including one containing a cyclic peptide), for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface root-mean-square-deviation measure.

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“…For preparation of the GPCR dataset used in this study, we examined all crystal structures of receptor-peptide and -peptidomimetic complexes form the largest Class A of GPCRs [24]. From the set of 9 identified crystal structures 2 were rejected due to the content of additional nonstandard amino acid residues in the peptide ligand chains, which could not be properly Supplementary Table S1.…”

Section: Gpcr Benchmark Datasetmentioning

confidence: 99%

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Badaczewska-Dawid

Kmiecik

Koliński

2020

Preprint

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The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein-peptide complex structures and model scoring. We evaluated the proposed protocol on the set of 7 different GPCR-peptide complexes (including one containing a cyclic peptide) for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface RMSD measure.

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Understanding Peptide Binding in Class A G Protein-Coupled Receptors

Cited by 26 publications

References 114 publications

Cloning of the first cDNA encoding a putative CCRFamide precursor: identification of the brain, eyestalk ganglia, and cardiac ganglion as sites of CCRFamide expression in the American lobster, Homarus americanus

Cloning of the first cDNA encoding a putative CCRFamide precursor: identification of the brain, eyestalk ganglia, and cardiac ganglion as sites of CCRFamide expression in the American lobster, Homarus americanus

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

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