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1 Acta Neurobiologiae Experimentalis

1 2011

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Molecular mechanism of interactions in human NPFF2-NPAF complex

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Kijkowska-Murak U. , Matosiuk D.

nr 1

The NPFF system represented by two receptors - NPFF1 and NPFF2, belongs to the class A (rhodopsin-like) G protein-coupled receptors. These receptors are specifically activated by different peptides arising from two precursors proNPFFA and proNPFFB, sharing a common PQRFamide C-terminus. Structure–activity relationship studies have revealed that NPFF2 receptors exhibit highest affinity for oligopeptides derived from proNPFFA precursor, such as neuropeptide FF itself and related peptides, as well as NPAF related peptides [1]. These peptides modulate the opioid system by exerting functional anti-opioid activity on neurons, but the mechanism of it is still unknown. Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation studies suggests an association between NPFF and MOP receptors. Moreover, NPFF2-MOP receptor heterooligomeric complex exists at the basal level and is differently modulated by NPFF and opioid agonists: the neuropeptide FF analog 1DMe promotes NPFF2-MOP receptor association, whereas the opioid agonist DAMGO disrupts it [2]. Thus, the aim of work was investigation of the molecular mechanisms of interactions in human NPFF2 - NPAF complex. For that purpose 3D models of human receptor NPFF2, as well as NPFF2 receptor endogenous selective peptidic ligand NPAF (AGEGLNSQFWSLAAPQRFNH2) was obtained. For modeling of the receptor protein homology modeling with YASARA STRUCTURE was used. For generating peptidic ligand structure experimental investigations on the neuropeptide AF structure [3] and de novo modeling method, as well as homology modeling were applied. In the following step molecular docking of the final model of ligand was performed with use of available tools: CLUSPRO and ROSETTADOCK. Complex of the ligand with the receptor protein was placed in a lipid bilayer and subjected to MD simulations. Procedure use allowed identification of the potential mechanism of interaction in the receptor – peptidic ligand complex. The results will be used to investigate the molecular mechanisms of interaction in human NPFF2 - MOP1 heterooligomeric complexes as an effect of the endogenous ligand of NPFF2 receptor binding.