Application of cryo-EM to understanding of GPCR structure, function and drug discovery

GPCRs are among the most important therapeutic drug target classes. The existing technical advances in GPCR cryo-EM provide a robust template for the generation of novel structures that could be used to facilitate new drug design and development. Moreover, increasing numbers of cryo-EM GPCR structures are being solved, both by our laboratories and others that enable innovative questions to be asked about how different drug chemotypes bind and how different ligands influence the conformational dynamics of the structures. Within this major Theme, using existing technologies and advances developed under Major Theme (i), structures will be determined for GPCRs that have validated and/or potential therapeutic interest. This will include new, first in class structures, and novel drug:GPCR complexes.

  

This work will be completed with the Monash University Node.

Project Areas

MIPS researchers are studying GPCRs from 3 of the major subclasses; Class A, Class B (particularly B1) and Class C. Receptor targets will be chosen based on alignment between potential industry partners and the host academic laboratories.

Novel GPCR structures

Although GPCRs account for ~30% of marketed drug targets, these account for only a small portion of potentially therapeutically important receptors. For many receptors, no structures current exist or the available structures are confined to a single receptor state (most also with only a single ligand). Within this project area, novel receptor structures will be determined, along with analysis of conformational dynamics of individual ligand receptor complexes. These novel structures can provide a template for future structure-directed drug discovery and development

  

Efficacy and complex stability

The ability to generate stable complexes of GPCRs with agonists and transducer proteins is influenced by ligand affinity and ligand efficacy, with the latter likely the critical factor for success. Despite this, there is only limited information on efficacy thresholds that need to be met and how these might vary with different technologies for complex stabilisation and solubilisation. However, early chemical hits and leads often have low potency. Understanding the relationship between efficacy and complex stability for an individual receptor is critical for integration of cryo-EM in drug discovery and development workflows. Moreover, in the context of the ability to form complexes with different transducers, projects could also potentially address the ability of structures to assist in understanding of biased agonists.

This project area will address this important knowledge gap for individual receptors.

   

Ligand affinity and potential for fragment screening

As we move towards new technical advances that will enable the determination of apo and inhibitor-bound GPCR structures by cryo-EM, research that addresses the capability of cryo-EM for understanding of binding of low affinity ligands (including fragments) will be increasingly important. This project area overlaps research on technical development of cryo-EM and will explore, for individual GPCRs of interest, the balance between affinity, solubility and the ability to achieve structural resolutions that could support drug discovery and development programs.