Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 1, Issue 1, Pages 32-49Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.8b00002
Keywords
amylin; CGRP; calcitonin receptor; GPCR; IAPP; RAMP
Categories
Funding
- Maurice Wilkins Centre for Molecular Biodiscovery
- Marsden Fund (Royal Society of New Zealand)
- Lottery Health (New Zealand)
- BBSRC (UK) [BB/M006883/1]
- Wellcome Trust senior investigator award [107927/Z/15/Z]
- NIH [R01GM104251]
- Royal Society Industrial Fellowship
- James Cook Research Fellowship from the Royal Society of New Zealand
- Sir Charles Hercus Fellowship from the Health Research Council (New Zealand)
- Auckland Medical Research Foundation
- GAANN fellowship from the U.S. Department of Education
- Wellcome Trust [107927/Z/15/Z] Funding Source: Wellcome Trust
- BBSRC [BB/M006883/1] Funding Source: UKRI
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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.
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