The lipid-associated 3D structure of SPA, a broad-spectrum neuropeptide antagonist with anticancer properties.
[D-Arg(1), D-Trp(5,7,9), Leu(11)] substance P (SPA) belongs to a family of peptides including antagonist G and SpD that act as broad-spectrum neuropeptide antagonists at several peripheral receptors. The lipid-induced structure of these peptides may be important for the receptor interactions of these analogs. Thus we describe the tertiary structure of SPA in the presence of sodium dodecylsulfate micelles at pH 5.0, and 25 degrees C as determined from two-dimensional (1)H-NMR data recorded at 500 MHz. The resulting three-dimensional structure can be generally described as two type IV nonstandard turns around Arg(1)*, Pro(2), Lys(3), and Pro(4) and Gln(6), Trp(7)*, Phe(8), and Trp(9)* residues, respectively, inserted into the interfacial region of the micelles (the asterisks denote D-form amino acid). These turns juxtapose the N- and C-termini of SPA and may form the basis of this peptide's unique ability to inhibit peptide receptor interactions at multiple receptor types.
Keire
David A
DA
CURE Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. dkeire@ucla.edu
Kumar
Mohanraja
M
Hu
Weidong
W
Sinnett-Smith
James
J
Rozengurt
Enrique
E
D000970:Antineoplastic Agents / Q000737:chemistry*; D002942:Circular Dichroism; D008567:Membranes, Artificial; D008823:Micelles; D008958:Models, Molecular; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D012967:Sodium Dodecyl Sulfate; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D008567:Membranes, Artificial; D008823:Micelles; D009479:Neuropeptides; D012996:Solutions; C102471:substance P, Arg(1)-Trp(5,7,9)-Leu(11)-; D014867:Water; D013373:Substance P; D012967:Sodium Dodecyl Sulfate