A5055786721- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Neuropeptides and Animal Physiology
- Olfactory and Sensory Function Studies
- Neurobiology and Insect Physiology Research
- Pancreatic function and diabetes
- Chemokine receptors and signaling
- Computational Drug Discovery Methods
- Biochemical Analysis and Sensing Techniques
- Protein Structure and Dynamics
- Cellular transport and secretion
- Multicomponent Synthesis of Heterocycles
- Peptidase Inhibition and Analysis
- Advanced Chemical Sensor Technologies
- Pharmacological Effects and Assays
- T-cell and B-cell Immunology
- Chemical Synthesis and Analysis
City of Hope
2021-2025
Beckman Research Institute
2021-2024
University of Copenhagen
2019-2022
Centre for Human Drug Research
2018
Leiden University
2018
Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by selective agonist. Therefore, we hypothesized integrated potency signaling properties provide unique pharmacological profile tailored improving broad metabolic control. Here, establish methodology calculating...
Abstract Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through related receptors (GLP-1R GLP-2R) which important drug targets for metabolic disorders Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding signal transduction between these remains elusive. Here we report electron microscopy human GLP-2R complex with...
In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of GIP system is desensitized, whereas this not case for GLP-1 system. This has raised an interesting discussion whether agonists or antagonists are most suitable future treatment T2DM together GLP-1-based therapies. Homozygous carriers receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased fracture risk and slightly blood glucose. Here, we present in-depth molecular pharmacological...
G protein–coupled receptors engage both proteins and β-arrestins, their coupling can be biased by ligands mutations. Here, to resolve structural elements mechanisms underlying effector the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of entire sequence with pharmacological profiling Gα q β-arrestin engagement mutant molecular dynamics simulations. We showed that AT1R involved a large number residues spread across receptor, whereas fewer regions...
The recent crystal structures of CC chemokine receptors 2 and 9 (CCR2 CCR9) have provided structural evidence for an allosteric, intracellular binding site. high conservation residues involved in this site suggests its presence most receptors, including the close homologue CCR1. By using [3H]CCR2-RA-[R], a high-affinity, CCR2 ligand, we report CCR1, where radioligand also binds with affinity. In addition, synthesis biological characterization series pyrrolone derivatives CCR1 CCR2, which...
Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification the incretin hormone glucagon-like peptide (GLP-1) alters capabilities of GLP-1 receptor (GLP-1R) by making it G protein internalization but was originally designed to DPP-4 resistance thereby prolong half-life GLP-1. Despite similar binding affinity, cAMP...
The glucagon receptor is dysregulated in metabolic disorders. Recent drug discovery has shown that agonists for the might be more promising as therapeutics. Allosteric modulation may pave an alternative way to initiate responses are required target these Here, we investigated allosteric communication mechanisms within using molecular dynamics simulations on five states. Results highlighted extracellular domain dynamic absence of orthosteric agonist. In presence a partial agonist, observed...
Naturally occurring missense variants of G protein-coupled receptors with loss function have been linked to metabolic disease in case studies and animal experiments. The glucagon receptor, one such is involved maintaining blood glucose amino acid homeostasis; however, loss-of-function mutations this receptor not systematically characterized. Here, we observed fewer than expected, as well lower allele diversity trait associations compared other class B1 receptors. We performed molecular...
Abstract A central challenge in olfaction is understanding how the olfactory system detects and distinguishes odorants with diverse physicochemical properties molecular configurations. Vertebrate animals perceive odors via G protein-coupled odorant receptors (ORs). In humans, ∼400 ORs enable sense of smell. The OR family composed two major classes: Class I are tuned to carboxylic acids while II ORs, representing vast majority human repertoire, respond a wide variety odorants. How recognize...
Glucagon-like peptide-2 (GLP-2) is a pro-glucagon-derived hormone secreted from intestinal enteroendocrine L cells with actions on gut and bones. GLP-2(1-33) cleaved by DPP-4, forming GLP-2(3-33), having low intrinsic activity competitive antagonism properties at GLP-2 receptors. We created radioligands based these two molecules.The methionine in position 10 of GLP-2(3-33) was substituted tyrosine (M10Y) enabling oxidative iodination, creating [125 I]-hGLP-2(1-33,M10Y) I]-hGLP-2(3-33,M10Y)....
Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate pharmacologically. Here, we identified conserved cluster of three aromatic receptor residues that anchors second extracellular loop (ECL2) top transmembrane helices (TM) 4 5 enables recognition both shared specific characteristics interacting chemokines. This was essential for activation several...
Abstract Our sense of smell enables us to navigate a vast space chemically diverse odor molecules. This task is accomplished by the combinatorial activation approximately 400 olfactory G protein-coupled receptors (GPCRs) encoded in human genome 1–3 . How odorants are recognized (ORs) remains mysterious. Here we provide mechanistic insight into how an odorant binds receptor. Using cryogenic electron microscopy (cryo-EM), determined structure active OR51E2 bound fatty acid propionate....
Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how truncation of full length CCL3(1–70) affects its activity at CCR1. Truncated CCL3(5–70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies G protein signaling determined by calcium release, cAMP IP3 formation. Small positive ago-allosteric ligands modulate the two CCL3 variants differently metal ion chelator bipyridine...
The glucose-dependent insulinotropic polypeptide (GIP) is a 42-residue metabolic hormone that actively being targeted for its regulatory role of glycemia and energy balance. Rational design ligands, however, has been tedious with no structural data the GIP receptor available. This study investigates structure function (GIPR), using homology model based on GLP-1 receptor. Molecular dynamics combined in vitro mutational were used to pinpoint residues play ligand binding and/or activation....
Abstract Cooperative interactions in protein-protein interfaces demonstrate the interdependency or linked network-like behavior of interface and their effect on coupling proteins. also could cause ripple allosteric effects at a distance interfaces. Although they are critically important it is challenging to determine which amino acid pair cooperative. In this work we have used Bayesian network modeling, an interpretable machine learning method, combined with molecular dynamics trajectories...