Mapping of the ligand-selective domain of the
            <i>Xenopus laevis</i>
            corticotropin-releasing factor receptor 1: Implications for the ligand-binding site

Dautzenberg, Frank M.; Wille, Sandra; Lohmann, Ragna; Spiess, Joachim

doi:10.1073/pnas.95.9.4941

Cited by 53 publications

(70 citation statements)

References 44 publications

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“…All of the extracellular domains contribute, in some degree, to the binding of the CRF peptide ligands. Interestingly, the ECD-1 of the Xenopus CRFR1 suffices to determine ligand specificity (23). Of special relevance for this work was our demonstration that a chimeric receptor in which the ECD-1 of CRFR1 replaced the ECD of the single transmembrane domain activin receptor displays high affinity binding for both a CRF antagonist and agonist (21).…”

Section: Discussionmentioning

confidence: 84%

“…Using mutational analyses, residues that affect binding of peptide or non-peptide antagonists as well as the selectivity of various CRF agonists have been identified in the extracellular and transmembrane domains of CRF receptors (22)(23)(24)(25)(41)(42)(43). All of the extracellular domains contribute, in some degree, to the binding of the CRF peptide ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Mutagenesis studies have identified regions of the CRF receptors that are implicated in differential recognition of agonists and antagonists, as well as in governing the ligand selectivity of the two types of receptors (21)(22)(23)(24)(25). We showed that a chimeric receptor in which the ECD-1 of CRFR1 replaced the ECD of the activin receptor, a single transmembrane receptor kinase (26), was capable of high affinity binding to both astressin and urocortin (21).…”

mentioning

confidence: 98%

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Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Perrin¹,

Fischer²,

Kunitake³

et al. 2001

Journal of Biological Chemistry

108

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Corticotropin releasing factor (CRF), 1 a 41-amino acid peptide, was identified initially on the basis of its primary role in the activation of the hypothalamic-pituitary-adrenal in response to stress. The CRF family of ligands includes sauvagine from frog and urotensin from fish as well as the additional mammalian family members, urocortin (1, 2), urocortin II (3, 4), and urocortin III (4, 5). Broader roles for CRF and its ligand family now involve effects on the cardiovascular, reproductive, gastrointestinal, immune, and central nervous systems (6 -8).The action of CRF and related ligands is initiated by binding to their receptors, which transduce an increase in intracellular cAMP. Thus far, two receptors, CRFR1 and CRFR2, have been cloned in mammals (9 -15). Homologous receptors have been identified in chicken (16), fish (17), and Xenopus (18) and a third receptor, CRFR3, with high levels of sequence identity to CRFR1, has recently been cloned in catfish (17). Both CRFR1 and CRFR2 exist as multiple splice variants and belong to the type B 7-transmembrane receptor family that includes receptors for growth hormone releasing factor, secretin, calcitonin, vasoactive intestinal peptide, glucagon, glucagon-like peptide, and parathyroid hormone (PTH). Receptors for the CRF ligand family have been characterized in the central nervous system, pituitary, gastrointestinal tract, epididymis, heart, gonads, and adrenals (6).The affinities of CRF and urocortin in binding to CRFR1 are nearly the same but in binding to CRFR2, urocortin is ϳ10 times more potent than CRF (19). Both urocortins II and III are highly selective in binding and activating CRFR2 compared with CRFR1 (4, 5). A synthetic peptide antagonist, astressin, binds with equally high affinity to CRFR1 and CRFR2 (19,20).The CRF receptor family consists of proteins with a relatively large first extracellular domain (ECD-1). Mutagenesis studies have identified regions of the CRF receptors that are implicated in differential recognition of agonists and antagonists, as well as in governing the ligand selectivity of the two types of receptors (21-25). We showed that a chimeric receptor in which the ECD-1 of CRFR1 replaced the ECD of the activin receptor, a single transmembrane receptor kinase (26), was capable of high affinity binding to both astressin and urocortin (21). The mode of receptor activation was explored by our study of a tethered peptide-receptor chimera in which the first 16 amino acids of CRF were substituted for the ECD-1 of CRFR1 (CRF (1-16)/R1 ⌬N ) (27). This chimera displayed continual signaling suggesting that the N-terminal third of CRF, when presented in proximity to the receptor, is able to cause activation.Biochemical characterizations of soluble ECD-1s include those of receptors for follicle stimulating hormone (28), luteinizing hormone/human chorionic gonadotropin (29), calcium (30), PTH (31), glucagon-like peptide-1 (32), and glutamate (33). The ECD-1 of the metabotropic glutamate receptor has

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

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Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Perrin¹,

Fischer²,

Kunitake³

et al. 2001

Journal of Biological Chemistry

108

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“…A two-domain behavior for ligand binding was also observed for the receptors (11,12). Analyses of mutant and chimeric receptors identified residues located mainly in the extracellular domains (ECDs) of CRF receptors that affect binding of peptide ligands (13)(14)(15)(16). Furthermore, we identified the major peptide binding site to be the ECD1 of CRF receptors (16,17) and determined the 3D NMR structure of the ECD1 of CRF-R2␤ (18).…”

mentioning

confidence: 99%

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Grace¹,

Perrin

Gulyás

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

126

175

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The corticotropin releasing factor (CRF) family of ligands and their receptors coordinate endocrine, behavioral, autonomic, and metabolic responses to stress and play additional roles within the cardiovascular, gastrointestinal, and other systems. The actions of CRF and the related urocortins are mediated by activation of two receptors, CRF-R1 and CRF-R2, belonging to the B1 family of G protein-coupled receptors. The short-consensus-repeat fold (SCR) within the first extracellular domain (ECD1) of the CRF receptor(s) comprises the major ligand binding site and serves to dock a peptide ligand via its C-terminal segment, thus positioning the N-terminal segment to interact with the receptor's juxtamembrane domains to activate the receptor. Here we present the 3D NMR structure of ECD1 of CRF-R2␤ in complex with astressin, a peptide antagonist. In the structure of the complex the C-terminal segment of astressin forms an amphipathic helix, whose entire hydrophobic face interacts with the short-consensus-repeat motif, covering a large intermolecular interface. In addition, the complex is characterized by intermolecular hydrogen bonds and a salt bridge. These interactions are quantitatively weighted by an analysis of the effects on the full-length receptor affinities using an Ala scan of CRF. These structural studies identify the major determinants for CRF ligand specificity and selectivity and support a two-step model for receptor activation. Furthermore, because of a proposed conservation of the fold for both the ECD1s and ligands, this structure can serve as a model for ligand recognition for the entire B1 receptor family.3D structure ͉ astressin ͉ corticotropin releasing factor ͉ NMR T he ability of the body to adapt to stressful stimuli and the role of stress maladaptation in human diseases has been intensively investigated. Corticotropin releasing factor (CRF) (1), a 41-residue peptide, and its three paralogous peptides, urocortin (Ucn) 1, 2, and 3, play important and diverse roles in coordinating endocrine, autonomic, metabolic, and behavioral responses to stress (2, 3). CRF family peptides and their receptors are also implicated in the modulation of additional central nervous system functions including appetite, addiction, hearing, and neurogenesis and act peripherally within the endocrine, cardiovascular, reproductive, gastrointestinal, and immune systems (4, 5). CRF and related ligands initially act by binding to their G protein-coupled receptors (GPCRs). These belong to the peptide hormone B1 family (family B1 GPCRs), comprising receptors for growth hormone releasing factor, secretin, calcitonin, vasoactive intestinal peptide, glucagon, glucagon-like peptide-1, and parathyroid hormone. Two CRF receptors, CRF-R1 and CRF-R2, have been cloned in mammals (6, 7).Structure activity studies of CRF showed that the first eight N-terminal residues of the hormone are necessary for GPCR signaling (1, 8), whereas the C-terminal (Ϸ15) residues are important for binding (9,10). A two-domain behavior for ligand binding was a...

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“…These compounds (see Figure 4e) are all allosteric modulators of the CRF 1 receptor (Hoare et al, 2003). The binding determinants for the compounds are located centrally within the TMD (Figure 3; Hoare et al, 2006;Liaw et al, 1997a), spatially separated from the binding determinants for CRF, which are located in extracellular-proximal regions of the receptor (the extracellular face of the TMD and within the ECD, Figure 3, (Dautzenberg et al, 1998;Hauger et al, 2006;Hoare et al, 2006;Liaw et al, 1997a, b). Binding of standard chemotype small molecules within the TMD stabilizes the TMD in the inactive state R (see Figure 2a), such that these compounds are classified as inverse agonists (Hoare et al, 2008).…”

Section: Gpcr Structure and Function: Allosteric Modulation In Drug Dmentioning

confidence: 99%

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

Grigoriadis

Hoare

Lechner

et al. 2008

Neuropsychopharmacol

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Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and g-aminobutyric acid receptors, and the Ca V 2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.

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Mapping of the ligand-selective domain of the Xenopus laevis corticotropin-releasing factor receptor 1: Implications for the ligand-binding site

Cited by 53 publications

References 44 publications

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Expression, Purification, and Characterization of a Soluble Form of the First Extracellular Domain of the Human Type 1 Corticotropin Releasing Factor Receptor

Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

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