A linear endothelin-1 analogue: solution structure of ET-1[Aib1,3,11,15, Nle7] by nuclear magnetic resonance spectroscopy and molecular modelling.
Two-dimensional nuclear magnetic resonance techniques and a combination of distance geometry and molecular dynamics calculations were utilised to determine the three dimensional solution structure of an ET-1 analogue, ET-1[Aib1,3,11,15, Nle7], in a methanol-d3/water co-solvent. The modelled structure shows that the peptide folds into a consistent alpha-helical conformation between residues Ser4-His16 while the C-terminus prefers no fixed conformation. Our studies confirm that the disulphide links which are normally associated with the endothelin family of neuropeptides are not important for the formation of a helical conformation in solution. This full length, modified, synthetic linear ET-1 analogue plays a vital role towards designing endothelin receptor agonists. Structure activity relationships are discussed in terms of the conformational features of the calculated structure.
Department of Chemistry, University of Edinburgh, UK.
C M
CM
Hewage
L
L
Jiang
J A
JA
Parkinson
R
R
Ramage
I H
IH
Sadler
D000595:Amino Acid Sequence; D003196:Computer Graphics; D004220:Disulfides; D019332:Endothelin-1 / Q000031:analogs & derivatives / Q000737:chemistry*; D006639:Histidine; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D017433:Protein Structure, Secondary; D012694:Serine; D012984:Software; D012996:Solutions
D004220:Disulfides; D019332:Endothelin-1; D012996:Solutions; C121499:endothelin-1, (Aib(1,3,11,15),Nle(7))-; D012694:Serine; D006639:Histidine