GPCRs in VR: Calcitonin Gene-Related Peptide (CGRP)
In this video, we continue to focus on GPCR receptors, particularly on calcitonin gene-related peptide receptors. Calcitonin Gene-Related Peptide (CGRP) is a 37 amino acid neuropeptide. CGRP levels are elevated during migraine attacks. Dysregulation of CGRP, a potent vasodilator, is directly implicated in the pathogenesis of migraine. CGRP binds to and signals through the CGRP receptor (CGRP-R), a heterodimer containing the calcitonin receptor like receptor (CLR), a class B GPCR, and RAMP1, a receptor activity-modifying protein.
Drugs act by blocking access to the peptide-binding cleft at the interface of CLR and RAMP1. These structures illustrate how small molecules bind to and modulate the activity of a class B GPCR, and highlight the challenges of designing potent receptor antagonists for the treatment of migraine and other class B GPCR-related diseases.
Reference:
Bucknell et al (2020). Structure-Based Drug Discovery of HTL22562: A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine. J Med Chem. 23;63(14):7906-7920. doi:
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