Structural studies of opioid peptides: A review of recent progress in x-ray diffraction studies

Abstract

The solid state structures of many opioid peptide agonists have been elucidated by x-ray diffraction analysis. Recently, the first structure of an opioid peptide antagonist has been determined. Theoretically, linear peptides can have many different backbone conformations, yet early x-ray studies (1983-1987) on enkephalin and its analogues showed only two different backbone conformations: extended and single beta-bend. In 1989 enkephalin was observed in a third conformation, a double beta-bend. Since that time diffraction studies have been completed on the rationally designed linear opioid peptide agonists DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) and DADLE (D-Ala2,D-Leu5-enkephalin) as well as on several cyclic enkephalin analogues including DPDPE (Tyr-[D-Pen-Gly-Phe-D-Pen]) and JOM-13 (Tyr-[D-Cys-Phe-D-Pen]). The most recent review of the x-ray studies on this class of compounds was written in 1988. This paper will update that review to include the results of studies completed since that time.

Solution structure of dynorphin A (1-17): a NMR study in a cryoprotective solvent mixture at 278 K

“…Introduction of restraints derived from intraresidue, sequential and medium range NOEs in DYANA [18] generated ten structures of dynorphin A with good values of the usual target function [18] out of 50 random generated initial conformers. All ten structures have similar values of the backbone torsion angles for the C-terminal part but diverge in the N-terminal region (message domain) even if there is some tendency to cluster around the conformers found in the crystal state for enkephalin [36]. Accordingly, it proved difficult to identify an average structure for the whole sequence.…”

Natural peptide analgesics: the role of solution conformation

“…It seems difficult, in general, to think of small linear peptides as molecules characterized by a 1574 R. Spadaccini and P. A. Temussi Conformation of opioid peptides forts of clever crystallographers, several structures of linear opioid peptides are now available [20, 21, 23 -33]. These structures are classified and dissected most efficaciously in a review by Deschamps et al [33]. Although no definite conclusion could be reached on their possible biological relevance, the solid-state structures of enkephalins, as determined by X-ray diffraction analysis, have revealed a limited number of backbone conformations.…”

Solution structure of human β-endorphin in helicogenic solvents: an NMR study

“…Without a detailed molecular model of i-endorphin it is not possible to propose mechanisms of interaction with opioid receptors that go beyond the conformational preferences of the message domain, thoroughly explored for enkephalins and some of their synthetic analogs [34]. Therefore, we have undertaken a systematic investigation of the conformational state of i-endorphin in several solvents, representative of either transport fluids or of the less polar environments presumed for the interior of a typical G protein-coupled receptor [35].…”