Conformational Dynamics of Amylin Receptors Revealed by Hydrogen–Deuterium Exchange Mass Spectrometry
Year: 2026
Type: article
Abstract: Receptor activity-modifying proteins (RAMPs) are critical modulators of class B1 G protein-coupled receptors (GPCRs), altering receptor pharmacology, trafficking, and signaling. The calcitonin receptor (CTR) forms heterodimers with each of the three RAMPs to generate amylin receptors (AMYRs) with distinct agonist selectivity and signaling profiles. Although recent cryo-electron microscopy (cryoEM) structures have advanced our understanding of AMYR architecture in fully active states, the dynamic and mechanistic basis of RAMP-dependent modulation of the CTR remains poorly understood. Here, we use hydrogen-deuterium exchange mass spectrometry (HDX-MS) to probe the conformational dynamics of the CTR alone and in complex with each RAMP in the apo (ligand-free) state. Our results reveal that RAMPs differentially influence the flexibility of key CTR domains, including the extracellular domain, transmembrane helices, and intracellular regions involved in G protein engagement. Furthermore, the RAMPs exhibit subtype-specific dynamic signatures, particularly within their transmembrane and C-terminal regions. Together, these findings reveal how RAMPs allosterically shape CTR conformational landscapes, providing a dynamic framework that links insights from static structural models to functional pharmacology.
DOI: 10.1021/jacs.5c20644
Institutions: Monash University, Hudson Institute of Medical Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: Mechanistic understanding of biased agonism and dimerisation for co-targeting incretin receptors for metabolic diseases, Probing the role of dynamics in protein modulation of GPCR phenotype , A personalised pharmacogenomic approach to inform autosomal dominant hypocalcaemia treatment, Dynamics of calcitonin family receptor activation, Structure, function and modulation of peptide hormone G protein-coupled receptors (GPCRs)
OpenAlex ID: W7154582973