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Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations

Xiaoli An, Qifeng Bai, Zhitong Bing, Huanxiang Liu, Xiaojun Yao
2021 Computational and Structural Biotechnology Journal  
Yao, Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations  ...  Abstract Activation of human free fatty acid receptor 1 (FFAR1, also called hGPR40) enhances insulin secretion in a glucose-dependent manner.  ...  Moreover, we have clarified the mechanism of positive cooperativity between the partial agonist and AgoPAM binding sites.  ... 
doi:10.1016/j.csbj.2021.07.008 fatcat:5r2amxgllvejvbbhsjex4ofzla

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

D. C.- H. Lin, Q. Guo, J. Luo, J. Zhang, K. Nguyen, M. Chen, T. Tran, P. J. Dransfield, S. P. Brown, J. Houze, M. Vimolratana, X. Y. Jiao (+3 others)
2012 Molecular Pharmacology  
Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation  ...  Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo.  ...  We are also thankful to Jenny Lu, Jeff Reagan, and Ralf Schwandner for providing the stable cell lines.  ... 
doi:10.1124/mol.112.079640 pmid:22859723 pmcid:PMC3477236 fatcat:xjcuxwjiyrd6patf5upkmgau6a

Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery

R. N. V. Krishna Deepak, Ravi Kumar Verma, Yossa Dwi Hartono, Wen Shan Yew, Hao Fan
2021 Pharmaceuticals  
and allosteric ligand binding sites, and molecular mechanisms of ligand binding.  ...  The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened  ...  Acknowledgments: This research was supported by Biomedical Research Council of Agency for Science, Technology and Research (A*STAR), Singapore (to H.F.).  ... 
doi:10.3390/ph15010012 pmid:35056070 pmcid:PMC8779880 fatcat:cqbgiz4sj5hz5kjbd4o2z7udwy

Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease

Abigail Basson, Ashley Trotter, Alex Rodriguez-Palacios, Fabio Cominelli
2016 Frontiers in Immunology  
The possibility that these effects may reflect a number of other interconnected (i.e., pantropic) mechanisms, activated in parallel, particularly concerning various bacterial metabolites, is in the process  ...  fatty acids; (3) the effect of diet on bile acid composition, and the modulator role of bile acids on the gut microbiota; (4) the impact of endogenous and exogenous intestinal micronutrients and metabolites  ...  Host genetics and gene expression modulate immune mechanism of microbial molecular pattern recognition to influence the diversity and functionality of local microbiota (11).  ... 
doi:10.3389/fimmu.2016.00290 pmid:27531998 pmcid:PMC4970383 fatcat:cfryycl6wfa6bdxoblz42pkbm4

The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type

Chiara Tarantelli, Eleonora Cannas, Hillarie Ekeh, Carmelo Moscatello, Eugenio Gaudio, Luciano Cascione, Sara Napoli, Cesare Rech, Andrea Testa, Chiara Maniaci, Andrea Rinaldi, Emanuele Zucca (+3 others)
2021 Exploration of Targeted Anti-tumor Therapy  
Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET  ...  Results: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC50) of 49 nmol/L.  ...  New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease. Haematologica. 2019;104:e256-9.  ... 
doi:10.37349/etat.2021.00065 fatcat:rnjkevbzrbf3bmi5d5pku6xsda

Free Communications (Oral Sessions)

2015 Journal of Pharmacological Sciences  
Here, we report novel activators of transient receptor potential canonical (TRPC) channels which regulate neuronal function via modulation of Ca 2+ signaling.  ...  However, its molecular mechanism remains unknown. We have analyzed a role for mDia in emotional changes induced by chronic stress.  ...  This study was undertaken using the mouse macrophage cell line RAW264.7 to gain insight into its anti-in ammatory mechanisms.  ... 
doi:10.1016/j.jphs.2015.07.028 fatcat:ryzemiuhbvcbng6ymlirll245e

Islet Biology/Insulin Secretion

2013 Diabetes  
Inhibitors of NOX activity reduce cellular ROS and the expression of NOX1. This observation suggests a feed-forward regulation of NOX1 in beta cells involving ROS elevation.  ...  We have also shown that NOX1 is upregulated by 12-lipoxygenase (12-LO) activity POSTERS ISLET BIOLOGY-APOPTOSIS in beta cells. 12-HETE (a product of 12-LO activity) upregulates NOX1 13±3fold (p<0.01) and  ...  During normal β-cell development, the cooperation of several transcription factors successively specifi es progenitor cells towards development into β-cells.  ... 
doi:10.2337/db13-2161-2296 pmid:23792721 fatcat:p7m2nxoezzdclcibpvn7zsrevy

Integrated Physiology/Obesity

2014 Diabetes  
We aimed to identify the molecular mechanism of severe IR in a 35-years-old nonobese woman who was diagnosed as having type 2 diabetes at age 31 during pregnancy.  ...  Tests for insulin and INSR antibodies were both negative. To explore the underlying molecular defect of IR, we sequenced the INSR gene.  ...  Those fi ndings would offer novel insights into the mechanisms of GCs induced fat distribution.  ... 
doi:10.2337/db14-1741-2092 fatcat:brgtjdu6yfcnxft766a2v3y6gi

Integrated Physiology/Obesity

2015 Diabetes  
UcOC was shown to correlate positively with CPR in GLT and CPR after meal taking (r = 0.32, p = 0.025; r = 0.29, p = 0.047).  ...  The average of age, duration of diabetes, BMI, and HbA1c of the subjects were 59.2 y.o., 7.8 years, 26.2 kg/m2 and 9.4%, respectively.  ...  cholesterol, and use of anti-hypertensive and lipid-lowering drugs.  ... 
doi:10.2337/db15-1929-2253 fatcat:x5hpu3ohqveifpkrby2rjwkp3m


2017 Respirology (Carlton South. Print)  
Acknowledgements: The grants were from Science and Technology Commission of Shanghai Municipality (No. 14411966400) and the National Science Foundation of China (NSFC81370109, 81670006).  ...  All the authors contributed to the study and had no conflict of interest.  ...  Further investigation of the underlying mechanisms may provide new insight into COPD pathogenesis.  ... 
doi:10.1111/resp.13206_193 fatcat:aocfzb5ulveorgtsqzamm5quee

Genome-wide homozygosity mapping in Congenital Hyperinsulinism of Infancy (CHI) :a family based study [article]

molecular mechanism at the basis of the disease..  ...  Mutations in ABCC8 gene are responsible of the 50-60% of focal and diffuse CHI patients, otherwise mutations in KCNJ11 are responsible for 10-15% of cases..Other less frequent molecular mechanism responsible  ...  molecular mechanism at the basis of the disease.  ... 
doi:10.13130/gessi-alessandra_phd2009-01 fatcat:7p4w77rukbdixn2jg4dvkmfexa

Characterisation of suppressor of cytokine signaling 1 regulation of type I interferon signaling

Rebecca Piganis
This thesis details the mechanism of SOCS1 regulation of type I IFN signaling as well as the consequences of this regulation in terms of its effect on IFNα induced STAT activation and the resultant transcriptional  ...  STAT1 is up-regulated by type I IFN in a broad range of immune cell types including thymic and peripheral T-cells, B-cells and macrphages whereas activation of STAT3 and STAT5 is more confined to the thymic  ...  A combination of ChIP-Seq studies with next generation sequencing of the RNA profile induced in the cell will also provide insight into how these STATs cooperatively regulate gene expression.  ... 
doi:10.4225/03/58b4e8a11950d fatcat:uuqnn2kleff6vmyygbvcmrnrdq

Nrg4 and Gpr120 signalling in brown fat

Anthony Okolo, Aylin C. Hanyaloglu, Malcolm G. Parker, Education Trust Fund (Nigeria), Imperial College London
These findings could provide insight into the requirements for Gpr120 function in BAT, the exploitation of which could generate ligands for therapeutic benefit and represents a promising opportunity to  ...  Gpr120 is a member of the superfamily of G protein-coupled receptors that is activated by long chain fatty acids.  ...  DISCLOSURES The authors declare that they have no conflicts of interest, financial or otherwise. AUTHOR CONTRIBUTIONS  ... 
doi:10.25560/26287 fatcat:j4vywh73jndkldlf5psbq52wt4

Synthesis of Structural and Fluorescently Labelled Peptidic Ligands for Optical Imaging of G Protein-Coupled Receptors

Mengjie Liu
Fluorescence imaging is capable of facilitating highly specific and non-invasive investigation of cellular and molecular events both in vitro and in vivo.  ...  This thesis describes the synthesis and pharmacological properties of structural and fluorescent peptide analogues that target the GPCRs of interest.  ...  A typical example is that feeding behaviour and the associated obesity appear to be regulated by multiple subtypes in highly complicated cooperating or counteracting mechanisms.  ... 
doi:10.4225/03/58c77bf8b2a95 fatcat:tjrnhtbsjvehhlfuopu22vnypi

Scienze e Tecnologie Agrarie Ambientali e Alimentari Ciclo XXIX Towards the development of nutrigenetic concepts in pigs by merging genomics, transcriptomics and metabolomics Presentata da: ANISA RIBANI Coordinatore Dottorato Relatore

Giovanni Dinelli, Luca Fontanesi
pathways would be one of the envisaged perspectives of application in pig nutrigenetics and, more generally, in livestock nutrition.  ...  Several approaches of target metabolomics, target re-sequencing of pig genome portions and RNA-seq have been performed, adding classical lab validations.  ...  Acknowledgements We thank ANAS for providing data and samples, Sara De Fanti (University of Bologna) for technical assistance, members of the Centre for Genome Biology for their support and Rita Casadio  ... 
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