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1

Molecular mechanism of interactions in human NPFF2-NPAF complex

100%
Kijkowska-Murak U., Matosiuk D.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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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.
2

Analysis of possible allosteric modulation of opioid signaling

61%
Bartuzi D., Kaczor A., Kijkowska-Murak U., Fidecka S., Kedzierska E., Matosiuk D.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Administration of classic orthosteric ligands of opioid receptors, like morphine, apart from inducing significant therapeutic effects such as analgesia, presents many disadvantages, with drug addiction and impairment of the breathing centre on the first place. However, allosteric modulation of these receptors could offer better selectivity among receptor subtypes and preservation of the physiological pattern of activation [1]. All in all, such compounds could bring more advantageous pharmacological profile, and decrease possibility of undesirable side effects. The aim of work was to investigate the mode of interaction of the unique ligands [2-5] with MOR and DOR opioid receptors. As premises of allosteric pockets existence appeared, establishment of a possible mode of interaction between ortho- and allosteric pocket became an consecutive aim. Models of the receptors were obtained with the method of homology modelling, using β2-adrenergic receptor as a template. These models were initially verified by rigid docking of rigid opiod receptors’ ligands (SIOM and naloxone). Best protein models were chosen for flexible dockings. Analysis of the results revealed that investigated compounds could be bound into two different pockets on the extracellular receptor’s surface near the orthosteric pocket. Location of those hypothetical binding sites suggests, that their interaction with ligands could significantly modulate function of the receptor. The hypothetical pocket located between extracellular parts of TM1, TM2 and TM7 seems to share important amino acids with orthosteric pocket. Moreover, the other hypothetical binding site is located in ECL2 region, and seems to be analogous to allosteric binding site discovered in muscarinic M2 receptor structure [6].
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