scholarly journals Membrane catalysis of peptide–receptor bindingThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 203-210 ◽  
Author(s):  
David N. Langelaan ◽  
Jan K. Rainey
Keyword(s):  
Electrostatic Interactions ◽  
Structural Changes ◽  
Peer Review Process ◽  
Membrane Binding ◽  
Peptide Ligands ◽  
Peptide Ligand ◽  
Membrane Catalysis ◽  
Membrane Mimetic ◽  
Anionic Micelles ◽  
G Protein Coupled

The membrane catalysis hypothesis states that a peptide ligand activates its target receptor after an initial interaction with the surrounding membrane. Upon membrane binding and interaction, the ligand is structured such that receptor binding and activation is encouraged. As evidence for this hypothesis, there are numerous studies concerning the conformation that peptides adopt in membrane mimetic environments. This mini-review analyzes the features of ligand peptides with an available high-resolution membrane-induced structure and a characterized membrane-binding region. At the peptide–membrane interface, both amphipathic helices and turn structures are commonly formed in peptide ligands and both hydrophobic and electrostatic interactions can be responsible for membrane binding. Apelin is the ligand to the G-protein coupled receptor (GPCR) named APJ, with various important physiological effects, which we have recently characterized both in solution and bound to anionic micelles. The structural changes that apelin undergoes when binding to micelles provide strong evidence for membrane catalysis of apelin–APJ interactions.

scholarly journals Vasopressin V2 is a promiscuous G protein-coupled receptor that is biased by its peptide ligands

2021 ◽  
Author(s):  
Franziska M. Heydenreich ◽  
Bianca Plouffe ◽  
Aurélien Rizk ◽  
Dalibor Milić ◽  
Joris Zhou ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Structural Changes ◽  
Peptide Ligands ◽  
Intrinsic Activity ◽  
Protein Activation ◽  
G Protein Activation ◽  
Added Benefit ◽  
V2 Receptor ◽  
G Protein Coupled

AbstractActivation of the G protein-coupled receptors by agonists may result in the activation of one or more G proteins, and in the recruitment of arrestins. The balance of activation of different pathways can be influenced by the ligand. Using BRET-based biosensors, we showed that the vasopressin V2 receptor activates or at least engages many different G proteins across all G protein subfamilies in response to its native agonist arginine vasopressin (AVP). This includes members of the Gi/o and G12/13 families that have not been previously reported. These signalling pathways are also activated by the synthetic peptide desmopressin and natural homologs of AVP, namely oxytocin and the non-mammalian hormone vasotocin. They demonstrated varying degrees of functional selectivity relative to AVP, as quantified using the operational model for quantifying ligand bias. Additionally, we modelled G protein activation as a Michaelis-Menten reaction. This approach provided a complementary way to quantify signalling bias, with an added benefit of clear separation of the effects of ligand affinity from the intrinsic activity of the receptor. These results showed that V2 receptor is not only promiscuous in its ability to engage several G proteins, but also that its signalling profile could be easily biased by small structural changes in the ligand.

NMR studies of CCK-8/CCK1 complex support membrane-associated pathway for ligand-receptor interaction

2002 ◽  
Vol 80 (5) ◽  
pp. 383-387 ◽  
Author(s):  
Craig Giragossian ◽  
Maria Pellegrini ◽  
Dale F Mierke
Keyword(s):  
G Protein ◽  
Structural Features ◽  
G Protein Coupled Receptors ◽  
Peptide Ligands ◽  
Receptor Interaction ◽  
Peptide Ligand ◽  
Receptor Subtype ◽  
Nmr Studies ◽  
Receptor Complexes ◽  
G Protein Coupled

The interaction of peptide ligands with their associated G-protein-coupled receptors has been examined by a number of different experimental approaches over the years. We have been developing an approach utilizing high-resolution NMR to determine the structural features of the peptide ligand, well-designed fragments of the receptor, and the ligand–receptor complexes formed upon titration of the peptide hormone. The results from these investigations provide evidence for a membrane-associated pathway for the initial interaction of peptide ligands with the receptor. Here, our results from the investigation of the interaction of CCK-8 with the CCK1 receptor are described. Our spectroscopic results clearly show that both CCK-8 and the regions of CCK1 with which it interacts are closely associated with the zwitterionic interface of the lipids utilized in our solution spectroscopic studies.Key words: G-protein-coupled receptors, NMR structural characterization, cholecystokinin, CCK-8, cholecystokinin receptor, subtype 1, CCK1, peptide hormones.

scholarly journals Biophysical characterization of G-protein coupled receptor–peptide ligand bindingThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 98-105 ◽  
Author(s):  
David N. Langelaan ◽  
Pascaline Ngweniform ◽  
Jan K. Rainey
Keyword(s):  
Membrane Proteins ◽  
G Protein ◽  
Peer Review Process ◽  
Titration Calorimetry ◽  
Peptide Ligand ◽  
Biophysical Characterization ◽  
Starting Point ◽  
G Protein Coupled ◽  
Selection Of

G-protein coupled receptors (GPCRs) are ubiquitous membrane proteins allowing intracellular responses to extracellular factors that range from photons of light to small molecules to proteins. Despite extensive exploitation of GPCRs as therapeutic targets, biophysical characterization of GPCR–ligand interactions remains challenging. In this minireview, we focus on techniques that have been successfully used for structural and biophysical characterization of peptide ligands binding to their cognate GPCRs. The techniques reviewed include solution-state nuclear magnetic resonance (NMR) spectroscopy, solid-state NMR, X-ray diffraction, fluorescence spectroscopy and single-molecule fluorescence methods, flow cytometry, surface plasmon resonance, isothermal titration calorimetry, and atomic force microscopy. The goal herein is to provide a cohesive starting point to allow selection of techniques appropriate to the elucidation of a given GPCR–peptide interaction.

Ion channels and G protein-coupled receptors as targets for invertebrate pest control: from past challenges to practical insecticides

2021 ◽  
Author(s):  
Yoshihisa Ozoe
Keyword(s):  
Ion Channels ◽  
G Protein ◽  
Pest Control ◽  
Gaba Receptors ◽  
Chloride Channels ◽  
Structural Changes ◽  
G Protein Coupled Receptors ◽  
Octopamine Receptors ◽  
Sites Of Action ◽  
G Protein Coupled

Abstract In the late 1970s, we discovered that toxic bicyclic phosphates inhibit the generation of miniature inhibitory junction potentials, implying their antagonism of γ-aminobutyric acid (GABA) receptors (GABARs; GABA-gated chloride channels). This unique mode of action provided a strong incentive for our research on GABARs in later years. Furthermore, minor structural changes conferred insect GABAR selectivity to this class of compounds, convincing us of the possibility of GABARs as targets for insecticides. Forty years later, third-generation insecticides acting as allosteric modulator antagonists at a distinctive site of action in insect GABARs were developed. G protein-coupled receptors (GPCRs) are also promising targets for pest control. We characterized phenolamine receptors functionally and pharmacologically. Of the tested receptors, β-adrenergic-like octopamine receptors were revealed to be the most sensitive to the acaricide/insecticide amitraz. Given the presence of multiple sites of action, ion channels and GPCRs remain potential targets for invertebrate pest control.

scholarly journals The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

2014 ◽  
Vol 92 (6) ◽  
pp. 431-440 ◽  
Author(s):  
Nigel A. Chapman ◽  
Denis J. Dupré ◽  
Jan K. Rainey
Keyword(s):  
G Protein ◽  
Cell Signalling ◽  
Wide Distribution ◽  
Peptide Ligand ◽  
Cellular Effects ◽  
Class A ◽  
Promising Therapeutic Target ◽  
Apelin Receptor ◽  
Obesity And Cancer ◽  
G Protein Coupled

The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein-coupled receptor with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation, strengthening of heart muscle contractility, angiogenesis, and regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ELABELA, was identified as having a crucial role in zebrafish (Danio rerio) embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity, and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about the mechanisms of peptide–AR activation. Additional complexity arises from modulation of the AR by 2 endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other G-protein-coupled receptors. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

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

scholarly journals The Spicy Story of Cannabimimetic Indoles

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6190
Author(s):  
Allyn C. Howlett ◽  
Brian F. Thomas ◽  
John W. Huffman
Keyword(s):  
Electrostatic Interactions ◽  
Cannabinoid Receptor ◽  
Binding Pocket ◽  
Herbal Products ◽  
The Public ◽  
Aromatic Stacking ◽  
Cb1 Cannabinoid Receptor ◽  
Colchicine Binding Site ◽  
Consumer Safety ◽  
G Protein Coupled

The Sterling Research Group identified pravadoline as an aminoalkylindole (AAI) non-steroidal anti-inflammatory pain reliever. As drug design progressed, the ability of AAI analogs to block prostaglandin synthesis diminished, and antinociceptive activity was found to result from action at the CB1 cannabinoid receptor, a G-protein-coupled receptor (GPCR) abundant in the brain. Several laboratories applied computational chemistry methods to ultimately conclude that AAI and cannabinoid ligands could overlap within a common binding pocket but that WIN55212-2 primarily utilized steric interactions via aromatic stacking, whereas cannabinoid ligands required some electrostatic interactions, particularly involving the CB1 helix-3 lysine. The Huffman laboratory identified strategies to establish CB2 receptor selectivity among cannabimimetic indoles to avoid their CB1-related adverse effects, thereby stimulating preclinical studies to explore their use as anti-hyperalgesic and anti-allodynic pharmacotherapies. Some AAI analogs activate novel GPCRs referred to as “Alkyl Indole” receptors, and some AAI analogs act at the colchicine-binding site on microtubules. The AAI compounds having the greatest potency to interact with the CB1 receptor have found their way into the market as “Spice” or “K2”. The sale of these alleged “herbal products” evades FDA consumer protections for proper labeling and safety as a medicine, as well as DEA scheduling as compounds having no currently accepted medical use and a high potential for abuse. The distribution to the public of potent alkyl indole synthetic cannabimimetic chemicals without regard for consumer safety contrasts with the adherence to regulatory requirements for demonstration of safety that are routinely observed by ethical pharmaceutical companies that market medicines.

Look Closely, the Beautiful May Be Small: Precursor-Derived Peptides in Plants

2019 ◽  
Vol 70 (1) ◽  
pp. 153-186 ◽  
Author(s):  
Vilde Olsson ◽  
Lisa Joos ◽  
Shanshuo Zhu ◽  
Kris Gevaert ◽  
Melinka A. Butenko ◽  
...  
Keyword(s):  
Cell Communication ◽  
Peptide Ligands ◽  
Biologically Active ◽  
Peptide Ligand ◽  
Long Distance ◽  
Signaling Systems ◽  
Experimental Approaches ◽  
Biologically Active Peptide ◽  
Subsequent Activation ◽  
Complex Signaling

During the past decade, a flurry of research focusing on the role of peptides as short- and long-distance signaling molecules in plant cell communication has been undertaken. Here, we focus on peptides derived from nonfunctional precursors, and we address several key questions regarding peptide signaling. We provide an overview of the regulatory steps involved in producing a biologically active peptide ligand that can bind its corresponding receptor(s) and discuss how this binding and subsequent activation lead to specific cellular outputs. We discuss different experimental approaches that can be used to match peptide ligands with their receptors. Lastly, we explore how peptides evolved from basic signaling units regulating essential processes in plants to more complex signaling systems as new adaptive traits developed and how nonplant organisms exploit this signaling machinery by producing peptide mimics.

Immune evasion in malaria: altered peptide ligands of the circumsporozoite protein

Parasitology ◽  
1997 ◽  
Vol 115 (7) ◽  
pp. 55-66 ◽  
Author(s):  
M. PLEBANSKI ◽  
E. A. M. LEE ◽  
A. V. S. HILL
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Peptide Ligands ◽  
Circumsporozoite Protein ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Amino Acid Residues ◽  
Liver Stage ◽  
Altered Peptide Ligands ◽  
Mhc Molecules

T cells are central to immunity in malaria. CD4+ helper T cells favour the generation of high-affinity antibodies that are effective against blood stages and they are necessary to establish immunological memory. The intrahepatic stage of infection can be eliminated by specific CD8+ cytotoxic T cells (CTL). Cytokines secreted by CD4+ T cells may also contribute to liver stage immunity. Evolution has selected varied mechanisms in pathogens to avoid recognition by T cells. T cells recognize foreign epitopes as complexes with host major histocompatibility (MHC) molecules. Thus, a simple form of evasion is to mutate amino acid residues which allow binding to an MHC allele. Recently, more sophisticated forms of polymorphic evasion have been described. In altered peptide ligand (APL) antagonism, the concurrent presentation of particular closely related epitope variants can prevent memory T cell effector functions such as cytotoxicity, lymphokine production and proliferation. In immune interference, the effect of the concurrent presentation of such related epitope variants can go a step further and prevent the induction of memory T cells from naive precursors. The analysis of immune responses to a protein of P. falciparum, the circumsporozoite protein (CSP), indicates that the malaria parasite may utilize these evasion strategies.

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