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Articles by Shane Wright
GLP-1R and GIPR crosstalk modulates insulinotropic signaling pathways
Keywords GLP-1R GIPR GPCR heterodimerization crosstalk stoichiometry obesity type 2 diabetes adverse drug events Introduction Obesity and diabetes are significant socio-economic challenges affecting millions of people worldwide.1 Treatment with the newer glucagon-like peptide-1 receptor (GLP-1R)-targeting drugs may result in substantial weight loss, approaching benefits achieved through bariatric surgery.2 Despite these advancements, it is still unclear how to best address the comorbidities...
Molecular mechanisms of native ligand selectivity in catecholamine G protein-coupled receptors
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Abstract Activation of G protein-coupled receptors (GPCRs) by extracellular ligands is crucial for cellular communication and modulates numerous physiological processes. Despite sharing highly similar orthosteric binding sites, catecholamine GPCRs exhibit exquisite selectivity for their native agonists, even among nearly identical chemical messengers. However, the molecular basis and evolution of receptor selectivity remain poorly understood.
By Nour Aldin Kahlous, Maiju K. Rinne, Xin Zhang, Yanying Li, Yue Chen, Kaixuan Gao, Christina A Bergqvist, Yi Wang, Alejandro Díaz-Holguín, Tore Bengtsson, Volker M Lauschke, Jyrki P. Kukkonen, Lucie Delemotte, Shane Wright, Xiangyu Liu, Dan Larhammar, Jens Carlsson, Aikaterini Motso, Hongda Sheng, Philip Ullmann
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Nature
Verified
Profiling of HCAR1 signaling reveals Gαi/o and Gαs activation without β-arrestin recruitment and the discovery of an allosteric agonist
Abstract Lactate was long considered a byproduct of glycolysis and associated with various harmful effects. However, the role of lactate was expanded with the finding that it also can act as a signaling molecule through the G protein-coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor was shown to be primarily expressed in adipocytes but is also expressed in many other tissues and cell types.
Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery
Abstract Protein phosphorylation is one of the most common mechanisms regulating cellular signaling pathways, and many kinases and phosphatases are proven drug targets. Upon phosphorylation, protein functions can be further regulated by the distinct isomerase Pin1 through cis-trans isomerization. Numerous protein targets and many important roles have now been elucidated for Pin1. However, no tools are available to detect or target cis and trans conformation events in cells.
A gut punch for PCOS
Abstract Suppression of GLP-1 release by a gut microbiota–derived metabolite induces polycystic ovary syndrome. SIGN UP FOR THE SCIENCEADVISER NEWSLETTER The latest news, commentary, and research, free to your inbox daily Polycystic ovary syndrome (PCOS) is an endocrine disorder that is characterized by hormonal imbalances, including hyperandrogenism, and that results in infertility and cardiovascular and metabolic abnormalities in women.
Conformation- and activation-based BRET sensors differentially report on GPCR-G protein coupling
Editor’s summary Bioluminescence resonance energy transfer (BRET)–based biosensors are commonly used to determine the specific G proteins that are activated by a particular G protein–coupled receptor (GPCR). Wright et al. found that the type of biosensor and other aspects of the experimental design, such as whether the receptor was tagged and the specific Gβ and Gγ subunits expressed in the cells, influenced whether the assay detected GPCR coupling to a particular Gα subunit.
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes - Nature Metabolism
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Abstract Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism.
By Hüsün S. Kizilkaya, Jakob S. Madsen, Peter Lindquist, Peter Gerlach, Lærke S. Gasbjerg, Jacek Mokrosiński, Brian Finan, Jonathan Campbell, David D’Alessio, Diego Perez-Tilve, Henrik T Sørensen, Jens S. Nielsen, Peter Damm, Oluf Borbye Pedersen, Allan Linneberg, Bolette Hartmann, Jens J Holst, Torben Frøstrup Hansen, Shane Wright, Volker M Lauschke, Niels Grarup, Alexander S. Hauser, Kimmie V. Sørensen, Jeannet Lauenborg
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Nature
Verified
Crimean–Congo haemorrhagic fever virus uses LDLR to bind and enter host cells - Nature Microbiology
Abstract Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean–Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids.
GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics - Nature Communications
Abstract G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events.
FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs
Despite exhibiting sequence and structural similarity to other classes of G protein–coupled receptors (GPCRs), class F family members are generally not considered to be prototypical GPCRs. Wright et al. found that the class F GPCR FZD 5 exhibited many of the functional characteristics of GPCRs. FZD 5 underwent a conformational change similar to that of conventional GPCRs upon ligand binding. Ligand binding also caused FZD 5 to activate signaling through Gα q -containing heterotrimeric G proteins.
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