G Protein–Coupled Receptors (GPCRs)

 

What are GPCRs?

GPCRs one of are the largest and most diverse class of membrane receptor found in eukaryotes. These receptors are responsible for receiving signals from proteins, lipids, peptides, even light energy, and eliciting a physiological response through subsequent activation or deactivation of different pathways in the body. GPCRs play diverse roles in biological functions, which has led to a high volume of research around GPCR-targeted therapies and drugs. Analysts estimate that over one-third of drugs on the market directly affect GPCR signaling pathways.

GPCRs Structure

GPCRRegardless of the multitude of signaling molecules that GPCRs bind, their structure has remained relatively unchanged through evolutionary history. Structurally, GPCRs form a heterotrimeric complex with G-proteins that are comprised of the 7-transmembrane receptor, the G-alpha subunit, and a beta-gamma subunit. The receptor has 7 alpha helices that traverse the plasma membrane and form an extracellular binding domain. The extracellular binding domain differs between receptors, but regardless of which ligand binds to the receptor, a conformational change of the GPCR results in release of the G-alpha subunit inside the cell by exchanging GDP with GTP. This allows the beta-gamma subunit to dissociate as well. Both the G-alpha and the beta-gamma subunits serve as signaling factors for a wide range of physiological pathways, from metabolic regulation to the interpretation of light in the retina.

GPCRs and Therapeutics

GPCRs are a significant class of therapeutic targets and are particularly relevant to drug research. Many widely used drugs target GPCR pathways or secondary messengers pathways associated with them. These pathways are among the most ubiquitous in the body and are directly responsible for many important physiological mechanisms.

In the recent past, scientists have used single domain antibodies to study GPCRs and their structures, particularly through X-ray crystallography. Using single domain antibodies as crystallization chaperones has allowed structural biologists to gain an even greater understanding of the receptors. The small size of these antibodies combined with their high specificity allows for creating a stable, unchanging structure that is more easily studied.

Developing antibodies against GPCRs can be challenging. These dynamic proteins are not easily targeted due to their many transmembrane domains and heterotrimeric structure. Keeping these proteins native through the immunization process is often the most difficult part of developing antibodies against them. Research and development at ProSci has worked with developing antibodies against these structures before, and is willing to take other projects of similar nature involving these impressive structures.