Resonance Energy Transfer Relates the Gas-Phase Structure and Pharmacological Activity of Opioid Peptides
Enkephalins are efficient pain-relief drugs that bind to transmembrane opioid receptors. One key structural param- eter that governs the pharmacological activity of these opioid peptides and is typically determined from condensed-phase structures is the distance between the aromatic rings of their Tyr and Phe residues. We use resonance energy transfer, detected by a combination of cold ion spectroscopy and mass spec- trometry, to estimate the Tyr–Phe spacing for enkephalins in the gas phase. In contrast to the condensed-phase structures, these distances appear to differ substantially in enkephalins with different pharmacological efficiencies, suggesting that gas- phase structures might be a better pharmacophoric metric for ligand peptides.