New project will give a better understanding of GPCRs
Professor Trond Ulven has received 6.2 mill DKK from Independent Research Fund Denmark for his project Bivalent ligands as tools for structural studies of dimeric GPCRs.
Trond Ulven describes the new project:
G protein-coupled receptors (GPCRs) are targets for a third of currently approved drugs, even if these targets constitute only a third of the ~350 GPCRs considered to have drug target potential.
Drug discovery targeting GPCRs have in recent years benefited from a revolution in technologies for obtaining high-resolution structures of the receptors in complex with ligands.
Cryogenic electron microscopy will be playing a main part in the project
Especially cryogenic electron microscopy (cryo-EM) has become important for rapid structure generation. However, the established cryo-EM technologies are still limited to activated GPCRs in complex with the relevant G protein, whereas structure elucidation of inactive GPCRs bound with antagonists, because of their small size, remains a challenge.
Unknown aspects of GPCR structures will be investigated
Furthermore, despite the massive amounts of structural information, several aspects of GPCRs remain obscure. One such aspect is their tendency to form dimers and oligomers, where only a limited number of structures are reported, and many questions still are open, such as the dynamic nature of dimers and oligomers and their mechanistic and physiological function.
How will your project solve the basic problems?
"Dimeric GPCRs are, due to their larger size, suitable for cryo-EM. In this project, we will develop new methods for obtaining cryo-EM structures of dimeric GPCRs with minimal artificial interference by taking advantage of bivalent ligands for stabilizing the structures.
Building on promising preliminary results, we will start with well-studied cases to establish the method and then expand it to other receptors."
How will your project help with drug development?
"The project is expected to result in improved methods for rapid high-resolution structural determination of homo- or heterodimeric GPCRs, including inactive GPCRs. It will also increase the understanding of dimeric GPCRs as a distinct class of drug targets and bivalent ligands as potential drug candidates. Thus, on the longer term, the project can facilitate the discovery of improved drugs".
Trond Ulven will be collaborating with Pontus Gourdon, Per Amstrup Pedersen, Karen Laurence Martinez and Elisabeth Rexen Ulven.
During the project three postdocs in medicinal chemistry, pharmacology and protein production/ structural biology will be employed.