Molecular modeling of the peptide agonist-binding site in a neurokinin-2 receptor

Indu R. Chandrashekaran, Gita Subba Rao, Sudha M. Cowsik

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


The neurokinin-2 receptor is a member of the rhodopsin family of G-protein coupled receptors, which represents one of the most relevant target families in small-molecule drug design. NK-2 receptors have been implicated in playing a pathophysiological role in asthma. Activation of the NK-2 receptor by its endogenous peptide agonist, tachykinins, is associated with diverse biological responses like bronchocon-striction, vasodepression, and regulation of endocrine functions. 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 NKA with its G-protein coupled receptor neurokinin-2 receptor has been developed. A three-dimensional model for the NK-2 receptor has been generated by homology modeling using rhodopsin as a template. A knowledge based docking of the NMR derived bioactive conformation of NKA to the receptor has been performed utilizing the ligand binding data obtained from the photoaffmity labeling and site-directed mutagenesis studies. The molecular model for the NKA/NK-2 receptor complex thus obtained sheds light on the topographical features of the binding pocket of the receptor and provides atomic 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-2 receptor selectivity.

Original languageEnglish
Pages (from-to)1734-1740
Number of pages7
JournalJournal of Chemical Information and Modeling
Issue number7
StatePublished - Jul 27 2009
Externally publishedYes


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