MORE ABOUT THE VEPRINTSEV LAB
Studying cell signalling
G protein-coupled receptors (GPCRs) represent the most abundant class of integral membrane proteins in the human genome. They account for roughly 40% of all prescription drugs, aimed at treating various diseases such as cardiac dysfunction, obesity, asthma, and others. In our lab, we develop approaches for incorporation of protein and systems dynamics GPCRs into drug discovery. The projects range from applying protein engineering to map allosteric connections in GPCRS, to structural studies of ligand-receptor complexes, to studying kinetics of signalling, to linking structural and pharmacological properties of ligands with receptor structure and signalling using advanced computational techniques.
MOLECULAR BASIS FOR GPCR SIGNALLING AT SINGLE AMINO ACID RESOLUTION
Understanding how GPCRs interpret binding of the ligand and transform it into activation of specific G proteins and recruitment of arrestins will help us to design better drugs.
We combine high through mutagenesis and advanced signaling assays to map the individual amino acids and molecular paths inside the receptor that make it work.
SINGLE MOLECULE GPCR PHARMACOLOGY
Studying how receptors signal “one-at-a-time”, on a signal molecule level, will allow us to understand how ligands and their binding kinetics affect signaling. This will help to fine-tune the kinetic properties of the candidate ligands for maximal therapeutic effect.
AI-ASSISTED LIGAND DESIGN
We combine structural information about receptors with the signaling maps derived from high throughput mutagenesis data to develop machine learning based predictors of the pharmacological properties of novel ligands. This approach has a potential to significantly speed up drug discovery.
DEVELOPING NOVEL LIGAND BINDING ASSAYS
Ligand binding is one of the key aspects of GPCR drug discovery. Measuring the kinetics of ligand binding provides new dimension for ligand screening. We develop novel florescence-based kinetic ligand binding assay based on time-resolved fluorescence (TR-FRET) and bioluminescence resonance energy transfer (BRET) in variety of formats. In addition, we also develop novel thermal stability based assays to detect ligand binding for receptors for which reporter ligands are not available.
GPCR FOLDING AND BIOGENESIS
A new project, led by Dr Eline Koers, involves studying the influence of chaperones on folding of GPCRs. Missense mutations in GPCRs are associated with disease. For example, the R137H variant of vasopressin V2 (V2R) receptor is folding-deficient and causes Nephrogenic Diabetes Insipidus. Despite the potential impact on human health, our current understanding of the process of GPCR folding is limited. Chaperones are known to aid the folding process and quality control of proteins. There are a number of indications that GPCRs also require chaperones for folding, maturation and trafficking, but little is known about the identity of these proteins. We try to elucidate the role of chaperons in GPCR folding.