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Home - 22.09.2011 - Biological Space 3/4: New Molecular Mechanism-Based Assays


Biological Space 3/4: New Molecular Mechanism-Based Assays

Thursday, September 22, 2011, 14:30 - 16:00

Receptor-HIT: Receptor heteromer investigation technology

K. Pfleger* University of Western Australia and Dimerix Bioscience (Perth, AU)

A receptor heteromer is a macromolecular complex composed of at least two (functional) receptor units with biochemical properties that are demonstrably different from those of its individual components [1]. Receptor heteromerization has been recognized as an important mechanism by which increased signalling diversity and regulation can be achieved for a variety of different receptors from receptor tyrosine kinases through to G protein-coupled receptors (GPCRs). The incredible potential of heteromerization to provide an entire new world of opportunities is also a daunting prospect for those in drug discovery who are looking for a place to start. Clearly there is a need for novel tools and technological approaches to steer a course through these largely uncharted waters.
The key is cell-based assay technologies that can provide information regarding ligand-dependent functional responses specific to the receptor heteromer, thus providing the ability to differentiate heteromer-specific pharmacology as distinct from signalling from co-expressed monomers or homomers. This in turn enables identification of ligands that result in heteromer-specific or heteromer-biased pharmacology. Establishing the so-called ‘biochemical fingerprint of the receptor heteromer’ [1] then enables profiles obtained in these cell systems to be correlated with pharmacology observed in native tissues and in vivo.
We have profiled both GPCR and receptor tyrosine kinase heteromers using the Receptor Heteromer Investigation Technology (Receptor-HIT) approach recently published for GPCRs as the GPCR-Heteromer Identification Technology (GPCR-HIT) [2-5]. As a consequence, we have gained novel insights into the functioning of heteromers, monitoring the recruitment of various intracellular proteins to the complexes following agonist stimulation in real-time and in live cells.
1.Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KDG, Pin JP, Volkow N, Waldhoer M, Woods AS and Franco R (2009) Nat Chem Biol 5: 131-134
2.Ayoub MA and Pfleger KDG (2010) Curr Opin Pharmacol 10: 44-52
3.Mustafa S, Ayoub MA and Pfleger KDG (2010) Drug Discov Today Technol 7: e77-e85
4.See HB, Seeber RM, Kocan M, Eidne KA and Pfleger KDG (2011) Assay Drug Dev Technol 9: 21-30
5.Mustafa S and Pfleger KDG (2011) JALA In Press

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