Effect of mutation of Phe 243 6.44 of the histamine H 2 receptor on cimetidine and ranitidine mechanism of action

Granja-Galeano, Gina; Zappia, Carlos Daniel; Fabián, Lucas; Davio, Carlos; Shayo, Carina; Fernández, Natalia Brenda; Monczor, Federico

doi:10.1016/j.bcp.2017.09.014

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…In the PIF motif, F240 6.44 displays an inward shift of P200 5.50 (Fig. 5c ), which is typical of class A GPCR activation 29 , 30 , suggesting that these residues help to relay the signal from the agonist to the cytoplasmic side of the GPCR 31 – 33 . Both the CWxP and the PIF motifs transmit signal from the orthosteric binding site through the allosteric sodium binding site and N/DPxxY motif to the DRY motif at the G protein interface.…”

Section: Resultsmentioning

confidence: 97%

Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

Park,

Kawakami,

Ishimoto

et al. 2023

Nat Commun

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Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce Gi/o signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson’s disease, the structural basis of ligand recognition and ligand-induced Gi-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2–Gi signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.

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Section: Resultsmentioning

confidence: 97%

Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

Park,

Kawakami,

Ishimoto

et al. 2023

Nat Commun

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“…Here, we aim to develop a model of GR interaction with coregulators and other components of a MTC that could describe and interpret differential ligand-specific transcriptional regulation of individual target genes. Our model is conceptually based on the cubic ternary complex receptor–occupancy model (Weiss et al, 1996), which has been extensively used before to describe the pharmacological behavior of multifactor complexes containing receptor proteins (Monczor et al, 2003; Fitzsimons et al, 2004; Tubio et al, 2010; Granja-Galeano et al, 2017). To experimentally test the model, we focused on gene transactivation, where the GR interacts with cofactors and DNA rather than acting by tethering mechanisms based on protein:protein interactions that influence the activity of other transcription factors without directly contacting the DNA (Newton and Holden, 2007).…”

Section: Introductionmentioning

confidence: 99%

A Model of Glucocorticoid Receptor Interaction With Coregulators Predicts Transcriptional Regulation of Target Genes

et al. 2019

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Regulatory factors that control gene transcription in multicellular organisms are assembled in multicomponent complexes by combinatorial interactions. In this context, nuclear receptors provide well-characterized and physiologically relevant systems to study ligand-induced transcription resulting from the integration of cellular and genomic information in a cell- and gene-specific manner. Here, we developed a mathematical model describing the interactions between the glucocorticoid receptor (GR) and other components of a multifactorial regulatory complex controlling the transcription of GR-target genes, such as coregulator peptides. We support the validity of the model in relation to gene-specific GR transactivation with gene transcription data from A549 cells and in vitro real time quantification of coregulator-GR interactions. The model accurately describes and helps to interpret ligand-specific and gene-specific transcriptional regulation by the GR. The comprehensive character of the model allows future insight into the function and relative contribution of the molecular species proposed in ligand- and gene-specific transcriptional regulation.

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Molecular switches in GPCRs

Filipek

2019

Current Opinion in Structural Biology

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Effect of mutation of Phe 243 6.44 of the histamine H 2 receptor on cimetidine and ranitidine mechanism of action

Cited by 3 publications

References 29 publications

Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2

A Model of Glucocorticoid Receptor Interaction With Coregulators Predicts Transcriptional Regulation of Target Genes

Molecular switches in GPCRs

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