Three-dimensional consensus structure of sst2-selective somatostatin (SRIF) antagonists by NMR.
The three-dimensional NMR structures of seven octapeptide analogs of somatostatin (SRIF), based on octreotide, with the basic sequence H-Cpa/Phe2-c[DCys3-Xxx7-DTrp/DAph(Cbm)8-Lys9-Thr10-Cys14]-Yyy-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Aph(Cbm)/Tyr/Agl(NMe,benzoyl) and Yyy being Nal/DTyr/Thr, are presented here. Most of these analogs exhibit potent and highly selective binding to sst2 receptors, and all of the analogs are antagonists inhibiting receptor signaling. Based on their consensus 3D structure, the pharmacophore of the sst2-selective antagonist has been defined. The pharmacophore involves the side chains of Cpa2, DTrp/DAph(Cbm)8, and Lys9, with the backbone for most of the sst2-selective antagonists comprised a Type-II' beta-turn. Hence, the sst2-selective antagonist pharmacophore is very similar to the sst2-selective agonist pharmacophore previously described.
Grace
Christy Rani R
CR
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Erchegyi
Judit
J
Reubi
Jean Claude
JC
Rivier
Jean E
JE
Riek
Roland
R
D000595:Amino Acid Sequence; D016384:Consensus Sequence; D003545:Cysteine; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D017481:Receptors, Somatostatin / Q000737:chemistry; D012974:Sodium Iodide; D013004:Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013912:Threonine
D009842:Oligopeptides; D017481:Receptors, Somatostatin; D013912:Threonine; D013004:Somatostatin; D012974:Sodium Iodide; D003545:Cysteine