His381 of the rat CCKB receptor is essential for CCKB versus CCKA receptor antagonist selectivity

Jagerschmidt, Alexandre; Guillaume-Rousselet, Nathalie; Vikland, Marie-Louise; Goudreau, Nathalie; Maigret, Bernard; Roques, B. P.

doi:10.1016/0014-2999(95)00676-1

Cited by 40 publications

(59 citation statements)

References 31 publications

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“…Those studies, however, were more indirect, utilizing the orthosteric radioligand based on the natural peptide that is known to bind to extracellular loop and tail regions rather than a radioligand that binds directly to the intramembranous docking site of these small molecules. Two of the residues identified as important in the current work (residues 6.51 and 7.39) have also been identified as important for the binding of the benzodiazepine antagonist L364,718 to the CCK1R (25,46,47). This is helpful in confirming the more general relevance of these residues for small molecule ligand binding to this receptor.…”

Section: Discussionsupporting

confidence: 66%

Molecular Basis for Binding and Subtype Selectivity of 1,4-Benzodiazepine Antagonist Ligands of the Cholecystokinin Receptor

Cawston

Lam

Harikumar

et al. 2012

Journal of Biological Chemistry

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Background: Allosteric ligands targeting cholecystokinin receptors are needed. Results: Stereochemically distinct iodinated 1,4-benzodiazepine antagonists of type 1 and 2 cholecystokinin receptors dock to analogous intramembranous pockets that have distinct shape and molecular determinants. Conclusion: The geometry of the binding pockets and specific residue interactions are unique for each receptor. Significance: The predictive power of these insights should be useful in the discovery of lead compounds and in their refinement.

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Section: Discussionsupporting

confidence: 66%

Molecular Basis for Binding and Subtype Selectivity of 1,4-Benzodiazepine Antagonist Ligands of the Cholecystokinin Receptor

Cawston

Lam

Harikumar

et al. 2012

Journal of Biological Chemistry

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“…Furthermore, the detrimental effect of the simultaneous presence of Asp at both the 2.50 and 7.49 loci on receptor expression is not observed in most other GPCRs studied (9,10,12,17,31 (9,10,12,14). Only the -opioid receptor is similar to the GnRH receptor in manifesting complete loss of binding with Asp present at both the H2 and H7 loci (11).…”

Section: Discussionmentioning

confidence: 93%

“…While the inter-related roles of these H2 and H7 side chains in receptor activation (9 -12) suggest that they constitute a structural and functional microdomain, this conclusion has been considered controversial (13,14). The initial study of this microdomain in the GnRH receptor reported that the presence of an Asp residue in both loci eliminated detectable binding.…”

mentioning

confidence: 99%

“…This result raised the possibility that charge repulsion was responsible for the observed phenotype. However, the presence of Asp at both positions in wild-type non-mammalian GnRH receptors (15,16) and in several other GPCRs (3) as well as in functional mutant GPCRs (9,10,14,17) indicates that the side chains in this microdomain, that are compatible with function, differ among GPCRs.…”

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confidence: 99%

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The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

Flanagan¹,

Zhou²,

Chi³

et al. 1999

Journal of Biological Chemistry

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Structural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp 2.50 and Asn 7.49 residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn 1.50 (53) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins.The gonadotropin-releasing hormone (GnRH) 1 receptor belongs to the rhodopsin-like family of G protein-coupled receptors (GPCR) (1). This family includes the light-sensitive opsins, protease-activated receptors, and receptors for neurotransmitters, peptides, and glycoproteins. High resolution structural data have not yet been obtained for any GPCR. However, projection maps of rhodopsin, amino acid sequence alignment, and computational modeling indicate that GPCRs have 7 membrane-spanning ␣-helices (2-6). There is a high degree of homology within the transmembrane helices and certain amino acids are highly conserved throughout the family (2, 3, 7). This diverse family shares the common function of propagating a signal across lipid membranes and the amino acid side chains which are conserved among the GPCRs are likely to constitute key structural motifs which subserve this universal GPCR function. Several models of GPCRs, including the GnRH receptor (4, 8), have been constructed as aids for investigating receptor structure-function relations. Molecular models of GPCRs can be used to integrate experimental observations and generate structural hypotheses. However, the complexity of these structures and the limited number of experimentally determined constraints can lead to inconsistent behavior of the models (4, 7). To overcome these limitations, we have pursued the approach of identifying discrete structural motifs within receptor models, which might constitute functional microdomains. The microdomains are characterized in detail and subsequently incorporated into whole receptor models. In the GnRH receptor, for exa...

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“…Data were analyzed using the Maximum Likelihood Method (ML) [26], and the bootstrap strength was supported by 1000 replicates for both in ML analysis. The complete amino acid sequences of each fungus were used to construct the phylogenic tree.…”

Section: Bioinformatics Analysismentioning

confidence: 99%

Molecular cloning and expression analysis of mevalonate pyrophosphate decarboxylase inAntrodia cinnamomea

Lin

Shao

et al. 2016

MATEC Web of Conferences

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Abstract. Mevalonate pyrophosphate decarboxylase (MVD) plays important roles in triterpenoid biosynthesis via the mevalonate pathway. A novel MVD gene was isolated and identified in Antrodia cinnamomea (Ac-mvd). The fulllength cDNA contained an open reading frame with a length of 1,209 bp and encoded a 402-amino acid polypeptide with a molecular mass of 43.3 kDa and a theoretical pI of 8.23. As incubation time was prolonged for 28 days, the triterpenoid content in the mycelium gradually increased and reached 39.192 ± 2.025 mg/g; the triterpenoid content of the fruiting body grew in the hay of Cinnamomum kanehirae (ACFB-CK), was 49.391 ± 2.675 mg/g, which was significantly different from other samples (P < 0.05). qRT-PCR revealed that the highest expression levels of Ac-mvd in the mycelium of Antrodia cinnamomea were detected on the 7th day. The expression levels gradually decreased as culture time was extended from 14 days to 42 days.

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His381 of the rat CCKB receptor is essential for CCKB versus CCKA receptor antagonist selectivity

Cited by 40 publications

References 31 publications

Molecular Basis for Binding and Subtype Selectivity of 1,4-Benzodiazepine Antagonist Ligands of the Cholecystokinin Receptor

Molecular Basis for Binding and Subtype Selectivity of 1,4-Benzodiazepine Antagonist Ligands of the Cholecystokinin Receptor

The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

Molecular cloning and expression analysis of mevalonate pyrophosphate decarboxylase inAntrodia cinnamomea

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