Conserved molecular switch interactions in modeled cardioactive RF-NH2 peptide receptors: Ligand binding and activation

Rasmussen, Monica; Leander, Megan; Ons, Sheila; Nichols, Robert C.

doi:10.1016/j.peptides.2015.07.012

Cited by 13 publications

(7 citation statements)

References 59 publications

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“…The breaking of these switches results in movement of the TM helices, which can activate the receptor (Trzaskowski et al, 2012). These switches are the same as those reported for the AKHR of Drosophila melanogaster , Tribolium castaneum, Anopheles gambiae , and Rhodnius prolixus (Rasmussen et al, 2015), suggesting that the activation mechanism of Schgr-AKHR may be the same.…”

Section: Resultssupporting

confidence: 81%

The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor

Jackson

Pavadai

GÄde

et al. 2019

PeerJ

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Background Neuropeptides exert their activity through binding to G protein-coupled receptors (GPCRs). GPCRs are well-known drug targets in the pharmaceutical industry and are currently discussed as targets to control pest insects. Here, we investigate the neuropeptide adipokinetic hormone (AKH) system of the desert locust Schistocerca gregaria. The desert locust is known for its high reproduction, and for forming devastating swarms consisting of billions of individual insects. It is also known that S. gregaria produces three different AKHs as ligands but has only one AKH receptor (AKHR). The AKH system is known to be essential for metabolic regulation, which is necessary for reproduction and flight activity. Methods Nuclear magnetic resonance techniques (NMR) in a dodecylphosphocholin (DPC) micelle solution were used to determine the structure of the three AKHs. The primary sequence of the S. gregaria AKHR was used to construct a 3D molecular model. Next, the three AKHs were individually docked to the receptor, and dynamic simulation of the whole ligand–receptor complex in a model membrane was performed. Results Although the three endogenous AKHs of S. gregaria have quite different amino acids sequences and chain length (two octa- and one decapeptide), NMR experiments assigned a turn structure in DPC micelle solution for all. The GPCR-ModSim program identified human kappa opioid receptor to be the best template after which the S. gregaria AKHR was modeled. All three AKHs were found to have the same binding site on this receptor, interact with similar residues of the receptor and have comparable binding constants. Molecular switches were also identified; the movement of the receptor could be visually shown when ligands (AKHs) were docked and the receptor was activated. Conclusions The study proposes a model of binding of the three endogenous ligands to the one existing AKHR in the desert locust and paves the way to use such a model for the design of peptide analogs and finally, peptide mimetics, in the search for novel species-specific insecticides based on receptor–ligand interaction.

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Section: Resultssupporting

confidence: 81%

The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor

Jackson

Pavadai

GÄde

et al. 2019

PeerJ

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show abstract

“…The breaking of these switches results in movement of the transmembrane helices, which can activate the receptor (Trzaskowski et al 2012). These switches are the same as those reported for the AKH receptor of Drosphilia melanogaster, Tribolium castaneum, A. gambiae and Rhodnius prolixus (Rasmussen et al 2015), suggesting that the activation mechanism of Schgr-AKHR may be the same. The DRY ionic lock between arginine and tyrosine is postulated to open and close during receptor activation.…”

Section: Analysis Of Molecular Switchessupporting

confidence: 78%

Peer Review #1 of "The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor (v0.2)"

Krishnan¹

2019

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Background. Neuropeptides exert their activity through binding to G-protein coupled receptors (GPCRs). GPCRs are well-known drug targets in the pharmaceutical industry and are currently discussed as targets to control pest insects. Here we investigate the neuropeptide adipokinetic hormone (AKH) system of the desert locust Schistocerca gregaria. The desert locust is known for its high reproduction, and for forming devastating swarms consisting of billions of individual insects. It is also known that S. gregaria produces three different AKHs as ligands but has only one AKH receptor. The AKH system is known to be essential for metabolic regulation, which is necessary for reproduction and flight activity. Methods. Nuclear magnetic resonance techniques (NMR) in a dodecylphosphocholin (DPC) micelle solution were used to determine the structure of the three AKHs. The primary sequence of the S. gregaria AKH receptor (AKHR) was used to construct a 3D molecular model. Next, the 3 AKHs were individually docked to the receptor, and dynamic simulation of the whole ligand-receptor complex in a model membrane was performed. Results. Although the three endogenous AKHs of S. gregaria have quite different amino acids sequences and chain length (two octa-and one decapeptide), NMR experiments assigned a turn structure in DPC micelle solution for all. The GPCR-ModSim program identified human kappa opioid receptor (hk-OR) to be the best template after which the S. gregaria AKHR was modeled. All three AKHs were found to have the same binding site on this receptor, interact with similar residues of the receptor and have comparable binding constants. Molecular switches were also identified; the movement of the receptor could be visually shown when ligands (AKHs) were docked and the receptor was activated. Conclusions. The study proposes a model of binding of the three endogenous ligands to the one existing AKH receptor in the desert locust and paves the way to use such a model for the design of peptide analogs and finally, peptide mimetics, in the search for novel species-specific insecticides based on receptor-ligand interaction.

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“…Among the repertoire of interactions between 26RFa (19–26) and the human QRFP receptor, the strongest intermolecular contact is predicted between the Arg 25 residue of the peptide and the Gln 125 residue located in the TM3 helix of the receptor (Neveu et al, ), which is known to play a key role in the structure and function of class‐A GPCR (Venkatakrishnan et al, ). Similar ligand–receptor binding interactions have been reported between two insect RFamide peptides, sulfakinin and dromyosuppressin, and their respective receptors (Bass et al, ; Rasmussen et al, ).…”

Section: Rfa/qrfp Receptor(s)supporting

confidence: 70%

The Arg–Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24

Leprince

Bagnol

Bureau

et al. 2017

British J Pharmacology

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This article, contributed by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee for the QRFP receptor, confirms the existing nomenclature for this receptor, and reviews our current understanding of its structure, pharmacology and functions, and likely physiological roles in health and disease. More information on this receptor can be found in the Concise Guide to PHARMACOLOGY The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross-reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N-terminally extended form glutamine RF-amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF-amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non-mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure-activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non-peptidic antagonists have been designed from high-throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP-QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.

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Conserved molecular switch interactions in modeled cardioactive RF-NH2 peptide receptors: Ligand binding and activation

Cited by 13 publications

References 59 publications

The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor

The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor

Peer Review #1 of "The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor (v0.2)"

The Arg–Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24

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