Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Giuseppe Deganutti, Silvia Atanasio, Roxana Maria Rujan, Patrick M Sexton, Denise L Wootten, Christopher Reynolds

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Abstract

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate Class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.
Original languageEnglish
Article number720561
JournalFrontiers in Molecular Biosciences
Volume8
DOIs
Publication statusPublished - 26 Aug 2021

Funder

BBSRC Grant: BB/M006883/1

Keywords

  • CGRP
  • CGRPR
  • GPCR
  • binding
  • molecular dynamics
  • supervised molecular dynamics
  • telcagepant

ASJC Scopus subject areas

  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Molecular Biology

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