Chemical Biology & Therapeutics
G-protein-coupled receptors (GPCRs) are linked to various diseases and are the target of many drug treatments. Structural understanding of disease-relevant GPCRs would be enormously valuable to guide structure-based drug discovery approaches. Crystals of GPCRs, in general, are difficult to obtain because of the intrinsic flexibility of the receptor and because of their structural heterogeneity. Recent developments in protein engineering, membrane protein crystallogenesis in mesophases and X-ray crystallography has yielded several new structures and opened new possibilities for biophysical characterization. Our interest is in applying some of these recent breakthroughs to further our mechanistic understanding of pharmaceutically-relevant human integral membrane protein targets and to develop further structural and biophysical tools that can be applied to a wide range of GPCR family members.
The focus of my lab is to produce, conformationally stabilize and purify GPCRs for X-ray crystallography and other biophysical analysis (such as NMR, SPR, ITC, Mass-spectroscopy and fluorescence spectroscopy), and to crystallize and determine GPCR structures in different functional states. We use several different approaches that have been used to obtain high-resolution structures of “active” (agonist occupied) and “inactive” (antagonist occupied/inverse agonist occupied) receptors. We are working with mesophases (lipid cubid phases & bicelles) in crystallogenesis. In the course of crystallogenesis, we aim also to develop in mesophase techniques to characterize GPCR functionality, stability and crystallizability in lipid matrices.
Key themes: conformationally trapped GPCRs for structure based drug design, use of meso in biophysical characterization of GPCRs and their lipid-bilayer environment. Nanobodies. Prospectively useful in LMW and biologics projects.
The crystallographic structure of the human adenosine A2A receptor in a high-affinity antagonist-bound state: implications for GPCR drug screening and design.
Jaakola VP, Ijzerman AP.
Curr Opin Struct Biol. 2010 Aug;20(4):401-14
Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.
Katritch V, Jaakola VP, Lane JR, Lin J, Ijzerman AP, Yeager M, Kufareva I, Stevens RC, Abagyan R.
J Med Chem. 2010 Feb 25;53(4):1799-809
The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.
Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC.
Science. 2008 Nov 21;322(5905):1211-7.
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