Identification of Two Serine Residues Involved in Agonist Activation of the β-Adrenergic Receptor

Strader, Catherine D.; Candelore, Mari R.; Hill, W. S.; Sigal, Irving S.; Dixon, Richard A. F.

doi:10.1016/s0021-9258(18)80035-7

Cited by 515 publications

(117 citation statements)

References 30 publications

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“…between this model and our model of ␦ opioid receptor originates from the outward shifts of helices II and V, the shift of the C-terminus of helix III, and from an almost one-turn shift of helices V and VI in the direction perpendicular to the membrane plane in the model of Baldwin et al (1997). As a result, and as discussed by the authors themselves, the model of Baldwin et al (1997) contradicts some experimental data, such as the observed formation of a Zn 2ϩ binding cluster in positions V:-1 and VI:27 and in positions V:3 and VI:27 (Elling et al, 1995;Thirstrup et al, 1996); formation of H-bonds between residues III:7, V:3, V:6, V:7 and catecholamine ligands (Strader et al, 1987(Strader et al, , 1988(Strader et al, , 1989Wess et al, 1991); interaction of Asp II:14 and Asn VII:17 (Zhou et al, 1994;Sealfon et al, 1995); and the contact of Gly III:11 and Phe VI:12 in rhodopsin (Han et al, 1996a,b). All of these experimental data are simultaneously satisfied in our models (the models are compared in more detail by Lomize et al, 1998).…”

Section: Models Of ␦ and Opioid Receptorsmentioning

confidence: 82%

“…The "average" model of the ␣-bundle is also in agreement with constraints experimentally derived by site-directed mutagenesis for other GPCRs, such as the proximity of Asp 397 (II:28) and Lys 583 (VII:3) in the lutropin/choriogonadotropin hormone receptor (Fernandez and Puett, 1996), Asn 87 (II:14) and Asn 318 (VII:17) in the gonadotropin-releasing hormone receptor (Zhou et al, 1994), Asp 120 (II:14) and Asn 396 (VII:17) in the 5-HT 2A receptor (Sealfon et al, 1995), Asp 125 (III:7) and Lys 331 (VII:4) in ␣ 1B -adrenergic receptors (Porter et al, 1996), and the formation of an artificial Zn 2ϩ -binding site by histidine residues incorporated in positions V:Ϫ1, V:3, and VI:27 in mutant NK-1 and opioid receptors (Elling et al, 1995;Thirstrup et al, 1996). The models of cationic amine receptors (Lomize et al, 1998) are consistent with accessibilities of residues from helices III, V, and VII to water-soluble probes (Javitch et al, 1995;Fu et al, 1996) and with a vast sample of site-directed mutagenesis data demonstrating, for example, the interaction of AspIII:7 with the protonated amine of ligands (Fraser et al, 1989;Javitch et al, 1995;Ho et al, 1992;Mansour et al, 1992Mansour et al, , 1997Porter et al, 1996;Savarese and Fraser, 1992;Strader et al, 1987Strader et al, , 1988Wang et al, 1991Wang et al, , 1993, the involvement of SerV:6 of ␤-adrenoreceptors and SerV:7 of ␣-adrenoreceptors in H-bond formation with catechol ligands, the importance of SerV:10 for ligand binding and activation (Strader et al, 1989;Wang et al, 1991;Hwa et al, 1997), and the proximity of the indole rings of Trp 109 (III:3) and Trp 330 (VII:8) of the ␤ 2 -adrenoreceptor to the azido group of iodoazidopindolol, an affinity label for ␤-adrenergic receptors (Wong et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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Opioid Receptor Three-Dimensional Structures from Distance Geometry Calculations with Hydrogen Bonding Constraints

Pogozheva

Lomize

Mosberg

1998

Biophysical Journal

164

210

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Three-dimensional structures of the transmembrane, seven alpha-helical domains and extracellular loops of delta, mu, and kappa opioid receptors, were calculated using the distance geometry algorithm, with hydrogen bonding constraints based on the previously developed general model of the transmembrane alpha-bundle for rhodopsin-like G-protein coupled receptors (Biophys. J. 1997. 70:1963). Each calculated opioid receptor structure has an extensive network of interhelical hydrogen bonds and a ligand-binding crevice that is partially covered by a beta-hairpin formed by the second extracellular loop. The binding cavities consist of an inner "conserved region" composed of 18 residues that are identical in delta, mu, and kappa opioid receptors, and a peripheral "variable region," composed of 19 residues that are different in delta, mu, and kappa subtypes and are responsible for the subtype specificity of various ligands. Sixteen delta-, mu-, or kappa-selective, conformationally constrained peptide and nonpeptide opioid agonists and antagonists and affinity labels were fit into the binding pockets of the opioid receptors. All ligands considered have a similar spatial arrangement in the receptors, with the tyramine moiety of alkaloids or Tyr1 of opioid peptides interacting with conserved residues in the bottom of the pocket and the tyramine N+ and OH groups forming ionic interactions or H-bonds with a conserved aspartate from helix III and a conserved histidine from helix VI, respectively. The central, conformationally constrained fragments of the opioids (the disulfide-bridged cycles of the peptides and various ring structures in the nonpeptide ligands) are oriented approximately perpendicular to the tyramine and directed toward the extracellular surface. The results obtained are qualitatively consistent with ligand affinities, cross-linking studies, and mutagenesis data.

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Section: Models Of ␦ and Opioid Receptorsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Opioid Receptor Three-Dimensional Structures from Distance Geometry Calculations with Hydrogen Bonding Constraints

Pogozheva

Lomize

Mosberg

1998

Biophysical Journal

164

210

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“…For all DOPRs (Figs S8–S10), three conserved serine residues S 5.42 , S 5.43 , and S 5.46 in TM5 were found, which may form hydrogen bonds with the hydroxyl groups in dopamine's catechol moiety 83–85 . For the DOPRs, the alignment shows that the C‐terminus typically harbors cysteine residues as seen in B. mori , D. melanogaster , and T. castaneum , which are possibly involved in palmitoylation.…”

Section: Discussionmentioning

confidence: 95%

Molecular and pharmacological characterization of biogenic amine receptors from the diamondback moth, Plutella xylostella

Liu

Zhan

et al. 2021

Pest Management Science

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BACKGROUD Insect biogenic amines play important roles in mediating behavioral and physiological processes. They exert their effects by binding to biogenic amine receptors (BARs), which are specific receptor proteins in the G‐protein‐coupled receptor superfamily. BAR genes have been cloned and characterized from multiple model insects, including Drosophila melanogaster, Anopheles gambiae, Bombyx mori, Apis mellifera and Tribolium castaneum. However, relatively little work has addressed the molecular properties, expression profiles, and pharmacological characterization of BARs from other insects, including important pests. RESULTS In this study, we cloned 17 genes encoding putative biogenic amine receptor proteins from Plutella xylostella, a global pest of Brassica crops. These PxBAR genes were five octopamine receptors (PxOA1, PxOA2B1, PxOA2B2, PxOA2B3, and PxOA3), three tyramine receptors (PxTAR1A, PxTAR1B, and PxTAR2), four dopamine receptors (PxDOP1, PxDOP2, PxDOP3, and PxDopEcR), and five serotonin receptors (Px5‐HT1A, Px5‐HT1B, Px5‐HT2A, Px5‐HT2B, and Px5‐HT7). All PxBARs showed considerable sequence identity with orthologous BARs, and phylogenetic analysis clustered the receptors within their respective groups while preserving organismal evolutionary relationships. We investigated their molecular properties and expression profiles, and pharmacologically characterized the dopamine receptor, PxDOP2. CONCLUSIONS Our study provides important information and resources on biogenic amine receptors from P. xylostella, which suggests potential target sites for controlling this pest species. © 2021 Society of Chemical Industry.

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“…lA), which have been shown by mutagenesis to be involved in ligand binding (Wess et al, 1991;Bluml et al, 1994). Residues Phe-182 and Ser-281 correspond to serines 204 and 319 in the hamster (32 adrenergic receptor, which are also involved in ligand recognition (Strader et al, 1989). His-250 is equivalent to His-265 in the NK1 receptor.…”

Section: Discussionmentioning

confidence: 99%

Site-directed Mutagenesis Identifies Residues Involved in Ligand Recognition in the Human A2a Adenosine Receptor

Kim

Wess

Rhee

et al. 1995

Journal of Biological Chemistry

201

308

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The A2a adenosine receptor is a member of the G-protein coupled receptor family, and its activation stimulates cyclic AMP production. To determine the residues which are involved in ligand binding, several residues in transmembrane domains 5-7 were individually replaced with alanine and other amino acids. The binding properties of the resultant mutant receptors were determined in transfected COS-7 cells. To study the expression levels in COS-7 cells, mutant receptors were tagged at their amino terminus with a hemagglutinin epitope, which allowed their immunological detection in the plasma membrane by the monoclonal antibody 12CA5. The functional properties of mutant receptors were determined by measuring stimulation of adenylate cyclase. Specific binding of [3H]CGS 21680 (15 nM) and [3H]XAC (4 nM), an A2a agonist and antagonist, respectively, was absent in the following Ala mutants: F182A, H250A, N253A, I274A, H278A, and S281A, although they were well expressed in the plasma membrane. The hydroxy group of Ser-277 is required for high affinity binding of agonists, but not antagonists. An N181S mutant lost affinity for adenosine agonists substituted at N6 or C-2, but not at C-5'. The mutant receptors I274A, S277A, and H278A showed full stimulation of adenylate cyclase at high concentrations of CGS 21680. The functional agonist potencies at mutant receptors that lacked radioligand binding were > 30-fold less than those at the wild type receptor. His-250 appears to be a required component of a hydrophobic pocket, and H-bonding to this residue is not essential. On the other hand, replacement of His-278 with other aromatic residues was not tolerated in ligand binding. Thus, some of the residues targeted in this study may be involved in the direct interaction with ligands in the human A2a adenosine receptor. A molecular model based on the structure of rhodopsin, in which the 5'-NH in NECA is hydrogen bonded to Ser-277 and His-278, was developed in order to visualize the environment of the ligand binding site.

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Identification of Two Serine Residues Involved in Agonist Activation of the β-Adrenergic Receptor

Cited by 515 publications

References 30 publications

Opioid Receptor Three-Dimensional Structures from Distance Geometry Calculations with Hydrogen Bonding Constraints

Opioid Receptor Three-Dimensional Structures from Distance Geometry Calculations with Hydrogen Bonding Constraints

Molecular and pharmacological characterization of biogenic amine receptors from the diamondback moth, Plutella xylostella

Site-directed Mutagenesis Identifies Residues Involved in Ligand Recognition in the Human A2a Adenosine Receptor

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