The same ligand binds upside-down to closely related receptors
A new study conducted in the Lynagh group shows that closely related neuropeptide receptors do not always recognize ligands in the same way. The work lays out the blueprint for ligand recognition in this receptor family.
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Receptors are proteins on the cell surface that recognize specific ligands 鈥� signaling molecules - outside the cell, and trigger changes inside the cell. Two receptors binding the same ligand are expected to do so in a similar manner, but a new article published in the challenges this view. The study, conducted by current and former Lynagh group members , , and , together with collaborator from Concept Life Science, show different binding modes for the same ligand in two closely related ionotropic receptors
The FMRFa-gated sodium channel family (FaNaC) is a group of ionotropic receptors, or ligand-gated ion channels, found in molluscs and annelid worms. Receptors in this family recognize the neuropeptide FMRFa. Curious about the molecular basis behind the importance of FMRFa in these animals, the team tested the activity of different FMRFa derivatives on mollusc and annelid FaNaCs. To their surprise, mollusc receptors could no longer recognize the neuropeptide after changes to the 鈥渇ront end鈥� of the neuropeptide, while annelid receptors could no longer recognize neuropeptides that were altered at the 鈥渂ack end鈥�. 鈥淭he fact that closely related ligand-gated channels that are indeed gated by the same peptide have such different binding modes really illustrates that it isn鈥檛 鈥渟afe to assume鈥� that closely related structures function in exactly the same way鈥�, first author Emily Claereboudt explains.
鈥淭his really illustrates that it isn鈥檛 鈥渟afe to assume鈥� that closely related structures function in exactly the same way鈥� 鈥� Emily Claereboudt
By combining mutagenesis with recent structural studies, the authors found that FMRFa wedges into its binding site in totally different orientations in the mollusc and annelid FaNaCs - a surprising explanation to their observations. 鈥淭he strength of this paper is really in the use of functional data hand in hand with the previously published structural data of these two FaNaC channels鈥�, Claereboudt says. 鈥淏y considering both approaches, in parallel, we were able to determine not only are the binding modes different, but that this they are actually flipped.鈥�
Fine-tuning the properties of the FaNaC ligand-binding sites turned out to be a rewarding process for Claereboudt and her colleagues, paving the way for new applications in the laboratory. 鈥淭he numerous, small manipulations made in this study are tedious work but lead to such good, tangible information鈥�, says group leader Timothy Lynagh. 鈥淲e are now using this in the lab to engineer new ligands and new receptors to produce pharmaco-genetic tools for use in diverse neurophysiology projects.鈥�
