Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that plays a major role in sensory neurotransmission. It is a major drug design target as antagonists can be used to treat migraine while agonists are cardioprotective. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and the type 1 transmembrane domain protein, receptor activity modifying protein (RAMP) 1. As a result of our recent 3.3 Å cryo-electron microscopy structure of the human CGRP receptor in complex with the CGRP peptide and the Gs-protein heterotrimer1, and photoaffinity labelling studies2, we have been able to study both the dynamics and activation of the CGRP receptor complex. Molecular dynamics simulations indicate that the G protein, the CGRP peptide and the RAMP, provide stability to the receptor complex, particularly the orientation of the CLR extracellular domain. Supervised molecular dynamics simulations give insight into the binding pathway of the CGRP peptide. The induced charge3 approach has been used to study the effect of polarization on the GPCR-ligand binding pathway. The work provides novel insight into the role of RAMPs in the activation of the CGRP receptor.

Structure, dynamics, and activation of the CGRP receptor, a medically important class B GPCR

2019 Spring National Meeting

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