NMR and structural model of dynorphin A (1-17) bound to dodecylphosphocholine micelles.
Dynorphin A (1-17) (dynorphin) acts preferentially and with high affinity at the kappa-opioid receptor, for which it is the natural, endogenous ligand. Interest in designing new ligands to interact at the kappa-opioid receptor is based in part on the desire to circumvent some of the problems associated with mu-opioid ligands such as morphine. The high-resolution structure of dynorphin in an environment which closely resembles its environment in vivo could be considered as an important lead for new drugs. The interactions that occur between dynorphin and a model membrane are potentially important, as peptide hormone activity is thought to be mediated by interactions with the cell membrane. Therefore, we have determined the high-resolution structures of dynorphin in a model membrane. Results from our laboratory have shown the existence of an alpha-helical region in dynorphin from residues Gly3 through Arg9 when bound to perdeuterated dodecylphosphocholine (DPC) micelles. In this report we show that dynorphin is bound to DPC micelles and describe a family of dynorphin structures that is alpha-helical from residues Gly3 through Pro10 and that contains a beta-turn from residues Trp14 through Gln17. A model of interaction with the micelle is also reported and is discussed in the context of hormone action in vivo. The structures were determined with 1D and 2D nuclear magnetic resonance spectroscopy, distance geometry in dihedral angle space, and restrained molecular dynamics simulations.
Tessmer
M R
MR
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.
Kallick
D A
DA
D000595:Amino Acid Sequence; D015195:Drug Design; D004399:Dynorphins / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism; D017510:Protein Folding; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D017473:Receptors, Opioid, kappa; D010767:Phosphorylcholine; C028810:dodecylphosphocholine; D004399:Dynorphins