Cryo-electron microscopy (cryo-EM) research has shed new light on the binding and activation mechanism of the CGRP receptor, contributing to greater understanding of the progression of the molecular events that lead to migraine.
The research, led by researchers at Monash University, Melbourne, Australia, and published in Science, show how the binding of CGRP to the receptor leads to receptor activation.
Lead author, Dr Tracy Josephs, explains that the small size of CGRP receptor proteins, and their mobility, have made it difficult to investigate the structure and dynamics of unmodified versions of the receptor.
However, in the new study, cryo-EM and hydrogen-deuterium exchange mass spectrometry (HDX-MS) were used to study the unmodified receptor in its apo state and in the presence of agonist ligand, but not transducer protein.
“Based on the structures and data from complementary biophysical techniques, we showed that initial binding of CGRP to the receptor caused unexpectedly small conformational changes in the most prevalent form of the receptor. It was the coordinated change in dynamics of the external (CGRP binding) face of the receptor and the intracellular face that was the key, and visualising this would not have been possible by other methods,” says Josephs.
Josephs TM, Belousoff MJ, Liang Y-L et al. Structure and dynamics of the CGRP receptor in apo and peptide-bound forms. Science 2021 Feb 18. Online ahead of print.