C-Terminal Analogues of Parathyroid Hormone:  Effect of C-Terminus Function on Helical Structure, Stability, and Bioactivity

Potetinova, Zhanna; Barbier, J.-R.; Suen, Tanya; Dean, Thomas R.; Gardella, Thomas J.; Willick, Gordon E.

doi:10.1021/bi060500q

Cited by 13 publications

(12 citation statements)

References 49 publications

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“…The modular behavior of the CRF receptors with the ECD1 as the major peptide binding domain is also reported for other members of the peptide hormone GPCR family such as parathyroid hormone (12,40,41,43,44) and the SCR motif of the ECD1 is predicted to be conserved in all of the ECD1s of the B1 family of GPCRs (18). The modular property is also present for various peptide hormones such as parathyroid hormone (45). Typically the N-terminal segment of the ligand is responsible for receptor signaling, whereas the C-terminal segment is an important determinant for the receptor binding (45,46) and may interact with the ECD1 of the receptor as evidenced by cross-linking (47).…”

Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

confidence: 65%

“…The modular property is also present for various peptide hormones such as parathyroid hormone (45). Typically the N-terminal segment of the ligand is responsible for receptor signaling, whereas the C-terminal segment is an important determinant for the receptor binding (45,46) and may interact with the ECD1 of the receptor as evidenced by cross-linking (47). Furthermore, the bioactive conformations of various peptide hormones are proposed to be of amphipathic helical nature (48), similar to the conformation observed for astressin.…”

Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

confidence: 99%

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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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Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

confidence: 65%

Section: Crf Ligand-receptor Interactions Have a Common Binding Modementioning

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

View full text Add to dashboard Cite

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“…Crystals of the purified MBP-PTH1R-ECD bound to a synthetic PTH fragment (residues [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] were grown in hanging drops containing a reservoir solution of 100 mM sodium cacodylate (pH 6.5) and 30% (vol/vol) polypropylene glycol P400 (PPG P400). Diffraction data were collected at 21-ID-D (LS-CAT) of the Advanced Photon Source at Argonne National Laboratory (Argonne, IL).…”

Section: Methodsmentioning

confidence: 99%

“…Studies with ligand variants and receptor/ligand photo cross-linking indicate that the Nterminal fragment of PTH (residues 1-14) binds to the transmembrane domain, albeit with low affinity, and that it is able of activating the receptor (26,27). The C-terminal fragment of PTH (residues 15-34) binds to the N-terminal ECD of the receptor to confer high affinity and specificity to the receptor (28,29). This ''two-domain'' model of PTH binding and activation is further supported by studies with chimeric ligands and receptors (30)(31)(32) and has since been demonstrated for other class B GPCR molecules (33)(34)(35).…”

mentioning

confidence: 99%

Molecular recognition of parathyroid hormone by its G protein-coupled receptor

Pioszak

2008

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

238

313

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Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-Å structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer ␣-␤-␤␣ fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.calcitonin ͉ crystal structure ͉ glucagon ͉ maltose-binding protein ͉ osteoporosis

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“…The hPTH (1-34) is defined as a 'two-domain model', in which the N-terminal region (residues 1-14, hPTH (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)) recognizes and activates the PTH1R by attaching to the extracellular loops and the juxtamembrane regions of its transmembrane domain [10]. The C-terminal region (residues 15-34, hPTH (15-34)) comprises a high-affinity binding domain that binds to the PTH1R N-terminal ECD, resulting in high receptor affinity and specificity [11].…”

Section: Introductionmentioning

confidence: 99%