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The Lipid-Associated 3D Structure of SPA, a Broad-Spectrum Neuropeptide Antagonist with Anticancer Properties

David A. Keire ^* , Mohanraja Kumar ^* , Weidong Hu , James Sinnett-Smith ^*  and Enrique Rozengurt ^* 

^* CURE: Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System, Los Angeles, California: Digestive Diseases Division, University of California Los Angeles School of Medicine, Los Angeles, California; and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California

Correspondence: Address reprint requests to David A. Keire, VA GLAHS, Bldg. 115, Rm. 111B, 11301 Wilshire Blvd., Los Angeles, CA 90073. Tel.: 310-478-3711, Ext. 41828; Fax: 310-268-4963; E-mail: dkeire{at}ucla.edu.

[D-Arg¹, D-Trp^5,7,9, Leu¹¹] 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°C as determined from two-dimensional ¹H-NMR data recorded at 500 MHz. The resulting three-dimensional structure can be generally described as two type IV nonstandard 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 peptide's unique ability to inhibit peptide receptor interactions at multiple receptor types.