Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2021 Sep 13

PMID 34513925

Citations 5

Authors

Giuseppe Deganutti

Silvia Atanasio

Roxana-Maria Rujan

Patrick M Sexton

Denise Wootten

Christopher A Reynolds

Affiliations

Soon will be listed here.

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.

Citing Articles

Topical application of calcitonin gene-related peptide as a regenerative, antifibrotic, and immunomodulatory therapy for corneal injury.

Zidan A, Zhu S, Elbasiony E, Najafi S, Lin Z, Singh R Commun Biol. 2024; 7(1):264.

PMID: 38438549 PMC: 10912681. DOI: 10.1038/s42003-024-05934-y.

Topical application of calcitonin gene-related peptide as a regenerative, antifibrotic, and immunomodulatory therapy for corneal injury.

Zidan A, Zhu S, Elbasiony E, Najafi S, Lin Z, Singh R Res Sq. 2023; .

PMID: 37609298 PMC: 10441448. DOI: 10.21203/rs.3.rs-3204385/v1.

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins.

Kotliar I, Lorenzen E, Schwenk J, Hay D, Sakmar T Pharmacol Rev. 2023; 75(1):1-34.

PMID: 36757898 PMC: 9832379. DOI: 10.1124/pharmrev.120.000180.

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss.

Ma X, Guo J, Fu Y, Shen C, Jiang P, Zhang Y Front Mol Neurosci. 2022; 15:1028125.

PMID: 36311029 PMC: 9596917. DOI: 10.3389/fnmol.2022.1028125.

Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors.

Lu J, Piper S, Zhao P, Miller L, Wootten D, Sexton P Int J Mol Sci. 2022; 23(15).

PMID: 35897648 PMC: 9331257. DOI: 10.3390/ijms23158069.

References

De Lean A, Stadel J, Lefkowitz R . A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. J Biol Chem. 1980; 255(15):7108-17. View

Castro M, Nikolaev V, Palm D, Lohse M, Vilardaga J . Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism. Proc Natl Acad Sci U S A. 2005; 102(44):16084-9. PMC: 1276049. DOI: 10.1073/pnas.0503942102. View

Salmaso V, Sturlese M, Cuzzolin A, Moro S . Exploring Protein-Peptide Recognition Pathways Using a Supervised Molecular Dynamics Approach. Structure. 2017; 25(4):655-662.e2. DOI: 10.1016/j.str.2017.02.009. View

Barwell J, Conner A, Poyner D . Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function. Biochim Biophys Acta. 2011; 1813(10):1906-16. PMC: 3228915. DOI: 10.1016/j.bbamcr.2011.06.005. View

Breeze A, Harvey T, Bazzo R, Campbell I . Solution structure of human calcitonin gene-related peptide by 1H NMR and distance geometry with restrained molecular dynamics. Biochemistry. 1991; 30(2):575-82. DOI: 10.1021/bi00216a036. View

Vanommeslaeghe K, MacKerell Jr A . Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing. J Chem Inf Model. 2012; 52(12):3144-54. PMC: 3528824. DOI: 10.1021/ci300363c. View

Hay D, Pioszak A . Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol. 2015; 56:469-87. PMC: 5559101. DOI: 10.1146/annurev-pharmtox-010715-103120. View

Moore E, Gingell J, Kane S, Hay D, Salvatore C . Mapping the CGRP receptor ligand binding domain: tryptophan-84 of RAMP1 is critical for agonist and antagonist binding. Biochem Biophys Res Commun. 2010; 394(1):141-5. DOI: 10.1016/j.bbrc.2010.02.131. View

Wootten D, Simms J, Miller L, Christopoulos A, Sexton P . Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci U S A. 2013; 110(13):5211-6. PMC: 3612682. DOI: 10.1073/pnas.1221585110. View

10.

Yin Y, de Waal P, He Y, Zhao L, Yang D, Cai X . Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors. J Biol Chem. 2017; 292(24):9865-9881. PMC: 5473240. DOI: 10.1074/jbc.M117.782987. View

11.

Sommer B . Membrane Packing Problems: A short Review on computational Membrane Modeling Methods and Tools. Comput Struct Biotechnol J. 2014; 5:e201302014. PMC: 3962210. DOI: 10.5936/csbj.201302014. View

12.

Moore E, Burgey C, Paone D, Shaw A, Tang Y, Kane S . Examining the binding properties of MK-0974: a CGRP receptor antagonist for the acute treatment of migraine. Eur J Pharmacol. 2008; 602(2-3):250-4. DOI: 10.1016/j.ejphar.2008.11.050. View

13.

Liang Y, Khoshouei M, Deganutti G, Glukhova A, Koole C, Peat T . Cryo-EM structure of the active, G-protein complexed, human CGRP receptor. Nature. 2018; 561(7724):492-497. PMC: 6166790. DOI: 10.1038/s41586-018-0535-y. View

14.

Cuzzolin A, Sturlese M, Deganutti G, Salmaso V, Sabbadin D, Ciancetta A . Deciphering the Complexity of Ligand-Protein Recognition Pathways Using Supervised Molecular Dynamics (SuMD) Simulations. J Chem Inf Model. 2016; 56(4):687-705. DOI: 10.1021/acs.jcim.5b00702. View

15.

Ma S, Shen Q, Zhao L, Mao C, Zhou X, Shen D . Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors. Mol Cell. 2020; 77(3):669-680.e4. DOI: 10.1016/j.molcel.2020.01.013. View

16.

Josephs T, Belousoff M, Liang Y, Piper S, Cao J, Garama D . Structure and dynamics of the CGRP receptor in apo and peptide-bound forms. Science. 2021; 372(6538). DOI: 10.1126/science.abf7258. View

17.

Zhou F, Zhang H, Cong Z, Zhao L, Zhou Q, Mao C . Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020; 11(1):5205. PMC: 7567103. DOI: 10.1038/s41467-020-18945-0. View

18.

Bissaro M, Bolcato G, Deganutti G, Sturlese M, Moro S . Revisiting the Allosteric Regulation of Sodium Cation on the Binding of Adenosine at the Human A Adenosine Receptor: Insights from Supervised Molecular Dynamics (SuMD) Simulations. Molecules. 2019; 24(15). PMC: 6695830. DOI: 10.3390/molecules24152752. View

19.

Neidigh J, Fesinmeyer R, Prickett K, Andersen N . Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry. 2001; 40(44):13188-200. DOI: 10.1021/bi010902s. View

20.

Aksoydan B, Durdagi S . Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of calcitonin gene-related peptide receptor (CGRPR) heterodimer. Comput Biol Med. 2021; 141:105130. DOI: 10.1016/j.compbiomed.2021.105130. View