Molecular Modeling of Neurokinin B and Tachykinin NK₃ Receptor Complex

Abstract

The tachykinin receptor NK₃ is a member of the rhodopsin family of G-protein coupled receptors. The NK₃ receptor has been regarded as an important drug target due to diverse physiological functions and its possible role in the pathophysiology of psychiatric disorders, including schizophrenia. The NK3 receptor is primarily activated by the tachykinin peptide hormone neurokinin B (NKB) which is the most potent natural agonist for the NK₃ receptor. NKB has been reported to play a vital role in the normal human reproduction pathway and in potentially life threatening diseases such as pre-eclampsia and as a neuroprotective agent in the case of neurodegenerative diseases. Agonist binding to the receptor is a critical event in initiating signaling, and therefore a characterization of the structural features of the agonists can reveal the molecular basis of receptor activation and help in rational design of novel therapeutics. In this study a molecular model for the interaction of the primary ligand NKB with its G-protein coupled receptor NK₃ has been developed. A three-dimensional model for the NK₃ receptor has been generated by homology modeling using rhodopsin as a template. A knowledge based docking of the NMR derived bioactive conformation of NKB to the receptor has been performed utilizing limited ligand binding data obtained from photoaffinity labeling and site-directed mutagenesis studies. A molecular model for the NKB-NK₃ receptor complex obtained sheds light on the topographical features of the binding pocket of the receptor and provides insight into the biochemical data currently available for the receptor.

The Tachykinin Peptide Neurokinin B Binds Copper Forming an Unusual [CuII(NKB)2] Complex and Inhibits Copper Uptake into 1321N1 Astrocytoma Cells

“…Each copper hyperfine resonance will be split into 2nI + 1 (I = 1) resonances from coupling to a number (n) of magnetically equivalent nitrogen nuclei. These resonances will also have a characteristic intensity pattern, for example, coupling to four magnetically equivalent nitrogen nuclei will result in nine 14 N hyperfine resonances with an intensity pattern of (1: Table 1 yields the second derivative spectrum in blue ( Figure 5c 4 ] center and suggests the presence of a neutral species, which is consistent with the lack of a peak in the mass spectrum.…”

“…These peaks are characteristic of an α-helical structure, which is consistent with previous structural studies and is thought to be a physiologically relevant state. 4,37,38 The addition of 0.5, 1.0, and 1.5 equiv of copper results in a loss of intensity of all peaks, and a plot of the absolute intensity of the negative peaks as a function of the copper equivalents added shows that copper addition beyond 0.5 equiv has little effect on the intensity ( Figure 6B). In accord with the visible CD and electronic absorption spectroscopy, this confirms a stoichiometry of 1:2 Cu II /NKB.…”

The evolution of tachykinin/tachykinin receptor (TAC/TACR) in vertebrates and molecular identification of the TAC3/TACR3 system in zebrafish (Danio rerio)

“…Notably, the TM3, TM6 and TM7 domains of TACR3s, which have been demonstrated to be critical for ligand recognition in mammals (Gether et al, 1993), are highly conserved in zebrafish and human. The residues (N138, N142, Y315, F342, and M346) in human TACR3 are considered to be important for NKB binding (Ganjiwale et al, 2011;Malherbe et al, 2008), and these residues are also found to be located in the zebrafish TACR3s according to their homologous positions on human TACR3 (Fig. 7).…”

Direct Regulation of Gonadotropin Release by Neurokinin B in Tilapia (Oreochromis niloticus)

“…The signature motif in tilapia was different from that of all other fish examined (Figure 1). The C-terminal motif of NKBs is important to the binding of NKBs to their cognate receptors (32). We further searched for NKB of other cichlids.…”