Novel sst(4)-selective somatostatin (SRIF) agonists. 4. Three-dimensional consensus structure by NMR.
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.
Grace
Christy Rani R
CR
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.
Koerber
Steven C
SC
Erchegyi
Judit
J
Reubi
Jean Claude
JC
Rivier
Jean
J
Riek
Roland
R
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
D008024:Ligands; D008565:Membrane Proteins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D013004:Somatostatin