title: Novel sst2-selective somatostatin agonists. Three-dimensional consensus structure by NMR.
abstract: The 3D NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II' beta-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating the biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8, and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is, therefore, different from that proposed by others for sst2/3/5 analogues.
authors.affiliation: Structural Biology Laboratory, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christy Rani R
authors.initials: CR
authors.lastname: Grace
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Steven C
authors.initials: SC
authors.lastname: Koerber
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
authors.forename: Roland
authors.initials: R
authors.lastname: Riek
mesh_terms: D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2