-mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity.

Surratt, Christopher K.; Johnson, Peter; Moriwaki, Akiyoshi; Seidleck, Brian K.; Blaschak, Carrie J.; Wang, Jia Bei; Uhl, George R.

doi:10.1016/s0021-9258(17)32028-8

Cited by 220 publications

(91 citation statements)

References 44 publications

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“…Two such attachment points are the carboxyl and imidazole groups of AspIII:7 and HisVI:20, respectively, the only polar groups situated at the bottom of the binding pocket in all three calculated opioid receptor models (␦, , and ). The importance of the AspIII:7 and HisVI:20 residues for binding opioid ligands has been clearly demonstrated by mutagenesis (Befort et al, 1996b;Mansour et al, 1997;Surratt et al, 1994). In the receptor models, these carboxyl and imidazole groups are arranged in such a way that they can interact simultaneously with the N ϩ and OH groups, respectively, of the Tyr 1 or tyramine group present in most opioid ligands.…”

Section: Ligand Dockingmentioning

confidence: 99%

“…Smaller alkaloids (such as morphine and naloxone), on the other hand, interact predominantly with "conserved" residues in the bottom of the binding cavity, leaving some free space around the ligand. The results of extensive structure-activity studies of JOM-13 and DPDPE analogs (Heyl and Mosberg, 1992a,b;Mosberg et al, 1994a,b;Haaseth et al, 1994) and mutagenesis data (Befort et al, 1996a,b;Hjorth et al, 1995;Meng et al, 1996;Pepin et al, 1997;Surratt et al, 1994;Valiquette et al, 1996) were used to verify the ligand docking.…”

Section: Ligand Bindingmentioning

confidence: 99%

“…The first group includes mutagenesis of residues that are near the binding pocket of the calculated models. Replacement of many residues in the "conserved" region of the binding pocket, which are involved in the models in the formation of H-bonds with polar groups of the ligands, affects the binding of numerous ligands from different structural classes (Befort et al, 1996a,b;Chakrabarti et al, 1997;Surratt et al, 1994;Mansour et al, 1997). In particular, in all opioid receptor models, AspIII:7 forms the ionic pair or hydrogen bond with N ϩ of all opioid ligands.…”

Section: Mutagenesis Datamentioning

confidence: 99%

“…This correlates with the deleterious effect of the AspIII:73 Asn substitution on receptor activation and the binding of ligands, especially agonists (morphine, bremazocine, and peptides), to and ␦ receptors (Surratt et al, 1994;Befort et al, 1996a). Furthermore, TyrIII:8, TrpVI:16, and HisVI:20, whose mutations have been demonstrated to affect ligand binding (Befort et al, 1996b;Surratt et al, 1994;Mansour et al, 1997), interact directly with different ligands in the models: TyrIII:8 forms a H-bond with the first peptide group of JOM-13 and other cyclic peptides and with the 14-OH group of morphinans; HisVI:20 forms a H-bond with the hydroxyl group of Tyr 1 of peptides and the tyramine moiety of alkaloids; TrpVI:16 interacts with the aromatic ring of Tyr 1 or ring A of alkaloids. The effect of Tyr(VII:11) substitution on ligand binding (Mansour et al, 1997) can be explained by its participation in the H-bond network with Asp(III:7), the key residue for electrostatic interaction with N ϩ of all opioid ligands.…”

Section: Mutagenesis Datamentioning

confidence: 99%

“…In addition, we have included in the models the tentative structures of the three extracellular loops, which were calculated by distance geometry. Although the ligand-binding pocket consists mainly of residues from the transmembrane ␣-bun-dle, the extracellular loops of opioid receptors have also been shown to be important for interactions with many ligands (Chen et al, 1995;Fukuda et al, 1995;Hjorth et al, 1995;Meng et al, 1995Meng et al, , 1996Minami et al, 1996;Onogi et al, 1995;Pepin et al, 1997;Varga et al, 1996;Valiquette et al, 1996;Wang et al, 1994Wang et al, , 1995Xue et al, 1994Xue et al, , 1995Zhu et al, 1996a,b), whereas the extracellular N-terminus can be deleted in and receptors (Kong et al, 1994;Surratt et al, 1994) or exchanged between receptor subtypes (Meng et al, 1996) without affecting the ligand binding.…”

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: Ligand Dockingmentioning

confidence: 99%

Section: Ligand Bindingmentioning

confidence: 99%

Section: Mutagenesis Datamentioning

confidence: 99%

Section: Mutagenesis Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Mu-opioid receptor is located on the plasma membrane of dendrites that receive asymmetric synapses from axon terminals containing leucine-enkephalin in the rat nucleus locus coeruleus

et al. 1996

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We have recently shown, by using immunoelectron microscopy, that the mu-opioid receptor (mu OR) is prominently distributed within noradrenergic perikarya and dendrites of the nucleus locus coeruleus (LC), many of which receive excitatory-type (i.e., asymmetric) synaptic contacts from unlabeled axon terminals. To characterize further the neurotransmitter present in these afferent terminals, we examined in the present study the ultrastructural localization of an antipeptide sequence unique to the mu OR in sections that were also dually labeled for the opioid peptide leucine-enkephalin (L-ENK). Immunogold-silver labeling for mu OR was localized to extrasynaptic portions of the plasma membranes of perikarya and dendrites. The mu OR-labeled dendrites were usually postsynaptic to axon terminals containing heterogeneous types of synaptic vesicles and forming asymmetric synaptic specializations characteristic of excitatory-type synapses. The majority of these were immunolabeled for the endogenous opioid peptide L-ENK. Some mu OR-labeled dendrites received synaptic contacts from unlabeled axon terminals in fields containing L-ENK immunoreactivity. In such cases, the mu OR-labeled dendrites were in proximity to L-ENK axon terminals that contained intense peroxidase labeling within large dense core vesicles along the perimeter of the axoplasm. These results indicate that L-ENK may be released by exocytosis from the dense core vesicles and diffuse within the extracellular space to reach mu OR sites on the postsynaptic dendrite or dendrites of other neighboring neurons. The present study also reveals that unlabeled terminals apposed to mu OR-labeled dendrites may contain other opioid peptides, such as methionine-enkephalin. These data demonstrate several sites where endogenous opioid peptides may interact with mu OR receptive sites in the LC and may provide an anatomical substrate for the LC's involvement in mechanisms of opiate dependence and withdrawal.

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Rostrocaudal variation in targeting ofN-methyl-D-aspartate and mu-opioid receptors in the rat medial nucleus of the solitary tract

2000

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N‐methyl‐D‐aspartate (NMDA) receptors and mu‐opioid receptors (MOR) have been implicated in gustatory and cardiorespiratory visceral reflexes, respectively involving second order sensory neurons in rostral and intermediate portions of the medial nucleus of the solitary tract (mNTS). To determine whether there are cellular sites suggesting functional interaction involving NMDA receptors and MOR in these regions, we examined their ultrastructural immunocytochemical localization by using antisera recognizing the functional subunit of NMDA receptors (NR1) or MOR in rat brain. In both mNTS subdivisions, NR1 labeling was prominently seen along membranes of cytoplasmic organelles in somata and large dendrites, as well as on asymmetric postsynaptic densities in small dendrites and dendritic spines. Many of these profiles also contained MOR immunoreactivity that was mainly distributed along extrasynaptic plasma membranes. Quantitative regional comparison showed that dendrites composed 64% (167 of 261) and 35% (137 of 390) of the dually labeled structures in the rostral and intermediate mNTS, respectively. In contrast, only 11% (28 of 261) of the total dually labeled profiles in the rostral, but 46% (180 of 390) of those in the intermediate mNTS were axon terminals. Many of the terminals containing NR1 and/or MOR were large and formed asymmetric synapses with multiple targets, resembling those features of known visceral afferents. Our results suggest that opioids, active at MOR in mNTS, modulate excitatory visceral reflexes involving mainly postsynaptic NMDA receptors in the rostral region. In addition, they suggest that similar mechanisms exist in the intermediate mNTS, where both NMDA receptors and MOR may differentially regulate the presynaptic release of glutamate from the visceral afferents. J. Comp. Neurol. 421:400–411, 2000. © 2000 Wiley‐Liss, Inc.

show abstract

-mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity.

Cited by 220 publications

References 44 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

Mu-opioid receptor is located on the plasma membrane of dendrites that receive asymmetric synapses from axon terminals containing leucine-enkephalin in the rat nucleus locus coeruleus

Rostrocaudal variation in targeting ofN-methyl-D-aspartate and mu-opioid receptors in the rat medial nucleus of the solitary tract

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