Comparison of the structures of the endothelin A receptor antagonists BQ123 and N-methyl leucine BQ123 with the crystal structure of the C-terminal tail of endothelin-1.
The functionally important regions of the cyclic pentapeptide endothelin A receptor antagonist BQ123 are shown to correlate with the structure of the C-terminal tail of endothelin-1, as found in the recently-determined X-ray crystal structure. Residues 18 and 21 of endothelin-1 are spatially juxtaposed such that they superpose extremely well with D-Asp and D-Trp of the antagonist, consistent with the residues on this surface of the endothelin helix being important for binding. This study provides new information on the three-dimensional nature of the endothelin A receptor binding site which may prove useful for rational drug design.
Peishoff
C E
CE
Department of Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Janes
R W
RW
Wallace
B A
BA
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D003460:Crystallization; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011487:Protein Conformation; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C096711:cyclo(tryptophyl-aspartyl-prolyl-valyl-N-methylleucyl); C072247:cyclo(Trp-Asp-Pro-Val-Leu)