Molecular Modeling of Neurokinin B and Neurokinin-3 Receptor Complex

Abstract

The Neurokinin-3 (NK-3) receptor is a member of the Rhodopsin family of G-protein coupled receptors. NK-3 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. NK-3 receptor is primarily activated by the tachykinin peptide hormone Neurokinin B (NKB), the most potent natural agonist for the NK-3 receptor. NKB has been reported to play a vital role in the normal human reproduction pathway, potentially life threatening disease such as pre eclampsia and as a neuroprotective agent in case of neurodegenerative diseases. Agonist binding to the receptor is a crucial event in initiating signaling and therefore 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 NK-3 has been developed. A three-dimensional model for the NK-3 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 the photo-affinity labeling and site- directed mutagenesis studies. A molecular model for the NKB-NK-3 receptor complex thus 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 results of the receptor modeling studies have been used to discuss the molecular determinants for NK-3 receptor selectivity.