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Molecular Signature for Receptor Engagement in the Metabolic Peptide Hormone Amylin

Bower, RL and Yule, L and Rees, TA and Deganutti, G and Hendrikse, ER and Harris, PWR and Kowalczyk, R and Ridgway, Z and Wong, AG and Swierkula, K and Raleigh, DP and Pioszak, AA and Brimble, MA and Reynolds, CA and Walker, CS and Hay, DL (2018) 'Molecular Signature for Receptor Engagement in the Metabolic Peptide Hormone Amylin.' ACS Pharmacology and Translational Science, 1 (1). 32 - 49. ISSN 2575-9108

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Abstract

The pancreatic peptide hormone, amylin, plays a critical role in the control of appetite, and synergizes with other key metabolic hormones such as glucagon-like peptide 1 (GLP-1). There is opportunity to develop potent and long-acting analogues of amylin or hybrids between these and GLP-1 mimetics for treating obesity. To achieve this, interrogation of how the 37 amino acid amylin peptide engages with its complex receptor system is required. We synthesized an extensive library of peptides to profile the human amylin sequence, determining the role of its disulfide loop, amidated C-terminus and receptor "capture" and "activation" regions in receptor signaling. We profiled four signaling pathways with different ligands at multiple receptor subtypes, in addition to exploring selectivity determinants between related receptors. Distinct roles for peptide subregions in receptor binding and activation were identified, resulting in peptides with greater activity than the native sequence. Enhanced peptide activity was preserved in the brainstem, the major biological target for amylin. Interpretation of our data using full-length active receptor models supported by molecular dynamics, metadynamics, and supervised molecular dynamics simulations guided the synthesis of a potent dual agonist of GLP-1 and amylin receptors. The data offer new insights into the function of peptide amidation, how allostery drives peptide-receptor interactions, and provide a valuable resource for the development of novel amylin agonists for treating diabetes and obesity.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 01 May 2018 09:36
Last Modified: 31 Mar 2021 22:15
URI: http://repository.essex.ac.uk/id/eprint/21918

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