On the Road to Finding the Right Key: Structural Characterisation of Three Active States of the Human Neuropeptide Y Type 4 Receptor (hY4R) at the Molecular Level
Marta Gozzi1, Daniel Huster1
1Leipzig University, Institute of Medical Physics and Biophysics, Leipzig, Germany
Human neuropeptide Y receptors (hYxR) are rhodopsin-like, peptide-binding G-protein coupled receptors (GPCRs), which modulate a plethora of biological functions (e.g. energy homeostasis, vasoconstriction, circadian rhythm), and also play a central role in the insurgence of several wide-spread pathologies such as cancer progression, obesity/anorexia and epilepsy. They are often referred to as membrane trafficking proteins, whose functions and dysfunctions are tightly dependent on the specific extra- and intracellular coupling partners, as well as on the type of lipid membrane in which they are embedded. Understanding this complex interplay of receptor structures/bound ligands/physical environment has received much attention in the biochemical and biophysical communities, especially over the last 20 years, often motivated by the urgent need to develop selective therapeutics, based on receptor-specific key–lock mechanisms. Here, we present our latest results on the structural dynamics of the human Y receptor sub-type 4 (hY4R), which is the only member of the hYxR family to show remarkable selectivity for one specific endogenous ligand, namely pancreatic polypeptide (PP), and which, surprisingly, has received very little attention compared to the rest of the hYxR family. Through cell-free expression strategies, we introduce site-specific isotopic labels at the receptor, which allow us to follow structural changes at the molecular level using solid-state NMR spectroscopy.
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