A5000218659- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Neuropeptides and Animal Physiology
- Pancreatic function and diabetes
- Peptidase Inhibition and Analysis
- Metabolism, Diabetes, and Cancer
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Pharmacological Effects of Natural Compounds
- Signaling Pathways in Disease
- Epigenetics and DNA Methylation
- Pharmacological Effects and Assays
- Fibroblast Growth Factor Research
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Neuroendocrine Tumor Research Advances
- Pharmacology and Obesity Treatment
- GDF15 and Related Biomarkers
- Helicobacter pylori-related gastroenterology studies
- Lipid Membrane Structure and Behavior
Novo Nordisk (Denmark)
2014-2025
Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and approved for once-daily treatment of diabetes as well obesity. The aim the present studies was design a once weekly GLP-1 by increasing affinity secure full stability against metabolic degradation. fatty acid moiety linking chemistry were key features high receptor (GLP-1R) potency obtaining prolonged exposure action analogue. Semaglutide selected optimal candidate. has two amino...
Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase insulin secretion and a lowering glucagon secretion; addition, they body weight systolic pressure heart rate. Using new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) important target organs humans monkeys. In pancreas, GLP-1R was predominantly localized β-cells with markedly weaker...
GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the receptor potentiates synthesis and release insulin pancreatic beta-cells a glucose-dependent manner. The belongs class B G-protein-coupled receptors, subfamily characterized by large N-terminal extracellular ligand binding domain. Exendin-4 are 50% identical, exendin-4 full agonist with similar affinity potency for receptor. We recently solved crystal structure domain...
Choosing a partner that fits G protein–coupled receptors (GPCRs) are responsible for transducing diverse signals from outside to inside cells. This process requires specificity both in ligand binding GPCRs and coupling between their intracellular partners, proteins. Qiao et al. determined the structure of human glucagon receptor (GCGR), type B GPCR, bound one two heterotrimeric proteins, s or i1 . GCGR mainly through , structures provide basis this specificity. Conformational changes GCGR,...
Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures full-length receptors were determined complex with their orthosteric agonist peptides, however, little known about extracellular domain (ECD) conformations the absence ligands, which has limited our understanding activation mechanism. Here, we report 3.2 Å resolution, peptide-free crystal structure human GLP-1R inactive...
Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, their signalling is regulated by peptide hormones. Using hybrid structural biology approach together with the ECD 7TM crystal structures glucagon receptor (GCGR), we examine relationship between full-length conformation ligand binding. Molecular dynamics (MD) disulfide crosslinking studies suggest that apo-GCGR can adopt both open closed associated extensive contacts...
In response to three highly conserved neuropeptides, neuropeptide Y (NPY), peptide YY, and pancreatic polypeptide (PP), four G protein-coupled receptors mediate multiple essential physiological processes, such as food intake, vasoconstriction, sedation, memory retention. Here, we report the structures of human Y1, Y2, Y4 in complex with NPY or PP, Gi1 protein. These reveal distinct binding poses upon coupling different receptors, reflecting importance conformational plasticity recognizing...
The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members class B are distinguished by their large extracellular domain, which works cooperatively with canonical seven-transmembrane (7TM) helical domain signal in response binding various peptide hormones. We have combined structure-based site-specific mutational studies molecular dynamics simulations a full-length model GLP-1R bound multiple ligand variants. Despite...
Obesity is a major and increasingly prevalent chronic metabolic disease with numerous comorbidities. While recent incretin-based therapies have provided pharmaceutical inroads into treatment of obesity, there remains an ongoing need for additional medicines distinct modes action as independent or complementary therapeutics. Among the most promising candidates, supported by phase 1 2 clinical trials, cagrilintide, long-acting amylin calcitonin receptor agonist. As such, understanding how...
The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled (GPCR) family and well-established target for treatment type 2 diabetes. N-terminal extracellular domain (ECD) GLP-1R important GLP-1 binding crystal structure GLP-1/ECD complex was reported previously. first GPCR transmembrane (TM) solved recently, but full length still not well understood. Here we describe molecular details antibody-mediated antagonism using both in vitro pharmacology x-ray...
Activation of the glucagon-like peptide-1 receptor (GLP-1R) upon ligand binding leads to release insulin from pancreatic cells. This strictly glucose-dependent process renders and its ligands useful in treatment type II diabetes mellitus. To enable a biophysical characterization vitro, we expressed human full-length GLP-1R cytosol Escherichia coli as inclusion bodies. After purification, refolding SDS-solubilized was achieved by exchange SDS against detergent Brij78 using an artificial...
Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal II β-turn motif might be feature GLP-1R. In contrast, recent publications reporting structure of full-length GLP-1R have shown N-terminus receptor-bound in α-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained...
Here, we describe the development of FGF21 analog zalfermin (NNC0194-0499, 15), intended for once-weekly sc dosing. Protein engineering was needed to address inherent druggability issues natural hormone. Thus, deamidation Asp121 solved by mutation glutamine, and oxidation Met168 leucine. N-terminal region degradation dipeptidyl peptidase IV prevented alanine residue elongation. To prevent inactivating metabolism fibroblast activation protein carboxypeptidase-like activity in C-terminal...
Glucagon-like peptide-1 (GLP-1) activates the GLP-1 receptor (GLP-1R), which belongs to family B of G-protein-coupled receptors. We previously identified a selective small molecule ligand, compound 2, that acted as full agonist and allosteric modulator GLP-1R. In this study, structurally related molecule, 3, stimulated cAMP production from GLP-1R, but not homologous glucagon (GluR). The selectivity encouraged chimeric approach identify domains important for 3-mediated activation A subsegment...