The lipid-associated 3D structure of SPA, a broad-spectrum-neuropeptide antagonist with anti-cancer properties
David A Keire 1*, Mohanraja Kumar 2, Weidong Hu 3, James Sinnett-Smith 1 and Enrique Rozengurt 1
1 CURE/UCLA: Digestive Diseases Research Center
2 The David Geffen School of Medicine at UCLA
3 Division of Immunology, The Beckman Research Institute of the City of Hope
* To whom correspondence should be addressed. E-mail: dkeire{at}ucla.edu.
Submitted on May 18, 2006
Revised on July 6, 2006
Accepted on 6 September 2006
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Abstract |
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[D-Arg1, D-Trp5,7,9, Leu11]substance P (SPA) belongs to a family of peptides including antagonist G and SpD that act as broad-spectrum neuropeptide antagonists (BNSAs) 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°C as determined from 2D 1H-NMR data recorded at 500 MHz. The resulting 3D structure can be generally described as two type IV non-standard turns around Arg1*, Pro2, Lys3, and Pro4 and Gln6, Trp7*, Phe8, and Trp9* 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 peptides' unique ability to inhibit peptide receptor interactions at multiple receptor types.
Key Words:
NMR, SDS micelles, circular dichroism, fluorescense, peptide-lipid interaction, tertiary structure
