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The mu-selective heptapeptide opioid dermorphin has two conformations around Phe3 psi with no head-to-tail
Jacques Riand1, Pierre Nicolas, Daniel Baron
1Laboratoire de Dynamique, Interactions et Réactivité UMR 7075,(CNRS-Université Paris 6), CNRS, 2 rue H. Dunant, 94320 Thiais, France.
Abstract:
The mu opioid heptapeptide Dermorphin (DRM) is under 70 % of trans forms for the Tyr(5)-Pro(6) peptide bond in solution (CDCl(3)/DMSO-d(6) 1/1 vol/vol). Variations of NOE integrals at 5 temperatures show apparent correlation times of 0.8 to 0.9 ns (at 280 K) in that mixed solvent. Four NOE between non-adjacent residues reveal a large population of folded structures. However, in trans DRM, 4 adjacent NOE Phe(3)/Gly(4) can only be explained by an equilibrium between folded (psi(3) > 0) and extended (psi(3) > 0) conformations. Simulated annealing modeling gave about 60% (psi(3) > 0) and 40% (psi(3) > 0) of these conformer populations. Trans DRM study and previous studies on the heptapeptide opioids, dermenkephalin (DREK) and deltorphin-I (delta selective), and DREK(1-4)-DRM(5-7) hybrid (mu selective), show in folded structures more backbone bending of the first 4 residues in the mu opioids than in the delta peptides. Also, the main difference between mu- and delta-opioid peptides is a large fraction of extended conformations in mu heptapeptides. Either bending of the N-terminus, or extension of the C-terminal part in mu-opioid heptapeptides prevent the head-to-tail interactions which allow delta-opioid peptides to bind selectively to the delta-opioid receptor.
Insights
Mu-opioid heptapeptides like Dermorphin adopt folded and extended conformations. This structural flexibility, particularly in mu-opioid peptides, influences receptor binding selectivity compared to delta-opioid peptides.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Opioid peptides are crucial for pain modulation and exhibit receptor selectivity.
- Dermorphin (DRM) is a mu-opioid heptapeptide with implications for understanding opioid receptor interactions.
Purpose of the Study:
- To investigate the solution conformation of Dermorphin (DRM).
- To elucidate the structural differences between mu- and delta-opioid peptides that dictate receptor selectivity.
Main Methods:
- Nuclear Overhauser Effect (NOE) spectroscopy at variable temperatures.
- Simulated annealing modeling to determine conformational populations.
Main Results:
- Dermorphin exists in a trans conformation with a significant population of folded structures.
- Analysis revealed an equilibrium between folded and extended conformations in trans DRM.
- Mu-opioid peptides exhibit greater backbone bending and a higher fraction of extended conformations than delta-opioid peptides.
Conclusions:
- The conformational dynamics of mu-opioid heptapeptides, including backbone bending and extended structures, prevent head-to-tail interactions necessary for delta-opioid receptor binding.
- Structural variations in mu- and delta-opioid peptides are key determinants of their selective receptor binding profiles.