National Doctoral Programme in
Informational and Structural Biology

Molecular Pharmacology of Adenosine Receptors: looking beyond the static crystal structures

Adenosine plays a central role in the neuromodulation of the central and peripheral nervous system (CNS/PNS). Adenosine initiates its effects through the activation of four heterotrimeric guanine nucleotide-binding (G protein) coupled receptors (GPCRs) family A subtypes: adenosine A-1, adenosine A-2A, adenosine A-2B and adenosine A-3 receptors. Each of these four receptors play an essential role in responding to adenosine in the CNS, regulating pain, cerebral blood flow, basal ganglia functions, respiration and sleep. Each adenosine receptor subtype is associated with a different secondary messenger system and each has its own unique pharmacological profile. The adenosine A-2A receptor subtype is mainly linked to effectors which result in the stimulation of cyclic AMP. All of the adenosine receptors including adenosine A-2A are activated by adenosine and inhibited by caffeine and other methylxanthine analogs such as theophylline. Development of subtype specific compounds could provide a mechanism for treating maladies such as pain, Parkinson disease, Huntington disease, asthma, seizures and many other neurological disorders. We recently solved the crystal structure of the human adenosine A-2A receptor in complex with a high affinity subtype-selective antagonist, ZM241385, to 2.6 Ånström resolution. This, second human GPCR solved up to date, reveals different binding mode from human beta2-adrenoreceptor : beta-blockers or rhodopsin : retinal complex, and shows a subtle repacking of the transmembrane helices relative to the beta-adrenoceptor and rhodopsin structures, combined by unique disulfide bonding in the extracellular site. Based on our new structure, we could generate better pharmacore for adenosine receptors and screen new lead compounds.

My group at Oulu Biocenter and Department of Biochemistry, University of Oulu, focus on structural and functional studies on adenosine receptors and their interaction partners using mutagenesis, molecular pharmacology and x-ray crystallography. We will use the expertise in the collaboration laboratories on GPCRs as well as our experience on adenosine class of GPCRs, to enable us to make progress on these challenging membrane protein systems.

Latest publications:

• Jaakola VP, Lane JR, Lin JY, Katritch V, Ijzerman AP, Stevens RC. (2010). Identification and characterization of amino acid residues essential for human A2A adenosine receptor : ZM241385 binding and subtype selectivity. J Biol Chem. 2010 Feb 10.
• Katritch V, Jaakola VP, Lane JR, Lin J, Ijzerman AP, Yeager M, Kufareva I, Stevens RC, Abagyan R. (2010). Structure-Based Discovery of Novel Chemotypes for Adenosine A(2A) Receptor Antagonists. J Med Chem. 2010 Jan 22.
• Jaakola VP & Stevens RC. (2009). G Protein-Coupled Receptor Structures. Handbook of Cell Signaling, 2nd Edition, R.A. Bradshaw and E.A. Dennis, Eds., Oxford: Academic Press, pp. 129-138.
• Jaakola VP, Griffith M.T., Hanson M.A., Cherezov V., Chien, E.Y.T., Lane, R. IJzerman, A.P., Stevens R.C. (2008). The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science. 2008 Nov 21.
• Hanson M.A., Cherezov V., Griffith M.T., Roth C.B., Jaakola V.-P., Chien E.Y., Velasquez J., Kuhn P., Stevens R.C. (2008). A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure. 2008 Jun.

Further information: homepage (www.biochem.oulu.fi)