Design of ET(B) receptor agonists: NMR spectroscopic and conformational studies of ET7-21[Leu7, Aib11, Cys(Acm)15].
In a previous report we have shown that the endothelin-B receptor-selective linear endothelin peptide, ET-1[Cys (Acm)1,15, Ala3, Leu7, Aib11], folds into an alpha-helical conformation in a methanol-d3/water co-solvent [Hewage et al. (1998) FEBS Lett., 425, 234-238]. To study the requirements for the structure-activity relationships, truncated analogues of this peptide were subjected to further studies. Here we report the solution conformation of ET7-21[Leu7, Aib11, Cys(Acm)15], in a methanol-d3/water co-solvent at pH 3.6, by NMR spectroscopic and molecular modelling studies. Further truncation of this short peptide results in it displaying poor agonist activity. The modelled structure shows that the peptide folds into an alpha-helical conformation between residues Lys9-His16, whereas the C-terminus prefers no fixed conformation. This truncated linear endothelin analogue is pivotal for designing endothelin-B receptor agonists.
Hewage
Chandralal M
CM
Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, 4, Ireland. chandralal.hewage@ucd.ie
Jiang
Lu
L
Parkinson
John A
JA
Ramage
Robert
R
Sadler
Ian H
IH
D015195:Drug Design; D019332:Endothelin-1 / Q000737:chemistry*; D016232:Endothelins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists*; D012997:Solvents; D013329:Structure-Activity Relationship
D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012997:Solvents; C476026:endothelin7-21(Leu7,Aib11,Cys(Acm)15)