title: Novel sst(4)-selective somatostatin (SRIF) agonists. 4. Three-dimensional consensus structure by NMR.
abstract: The three-dimensional NMR structures of eight cyclic octapeptide analogues of somatostatin (SRIF) are described. These analogues, with the basic sequence H-c[Cys(3)-Phe(6)-Xxx(7)-Yyy(8)-Lys(9)-Thr(10)-Zzz(11)-Cys(14)]-OH (the numbering refers to the position in native SRIF), with Xxx(7) being Phe/Ala/Tyr, Yyy(8) being Trp/DTrp/D-threo-beta-Me2Nal/L-threo-beta-Me2Nal, and Zzz(11) being Phe/Ala, exhibit potent and highly selective binding to human SRIF type 4 (sst(4)) receptors. The conformations reveal that the backbones of these analogues do not have the usual type-II' beta-turn reported in the literature for sst(2)-subtype-selective analogues. Instead, the structures contain a unique arrangement of side chains of Yyy(8), Lys(9), and Phe(6) or Phe(11). The conformational preferences and results from biological analyses of these analogues (parts 1-3 of this series, Rivier et al., Erchegyi et al., and Erchegyi et al., J. Med. Chem. 2003, preceding papers in this issue) allow a detailed study of the structure-activity relationship of SRIF. The proposed consensus structural motif at the binding pocket for the sst(4)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, a lysine side chain, and another aromatic ring. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing model suggested for sst(2)/sst(5) selectivity.
authors.affiliation: Structural Biology Laboratory and The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Christy Rani R
authors.initials: CR
authors.lastname: Grace
authors.forename: Steven C
authors.initials: SC
authors.lastname: Koerber
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
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; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000737:chemistry*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D013004:Somatostatin