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Modulation of Kinase-Inhibitor Interactions by Auxiliary Protein Binding: Crystallography Studies on Aurora A Interactions with VX-680 and with TPX2

GlaxoSmithKline

(RECEIVED May 21, 2008; ACCEPTED July 22, 2008)

VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the co-crystal structure of AurA/TPX2/VX-680 at 2.3 Å resolution. In the crystal structure, VX-680 binds to the active conformation of Aur A. The glycine-rich loop in AurA adopts a unique bent conformation, forming a - interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically-relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multi-protein complexes may be beneficial to discovery and optimization of enzyme inhibitors as therapeutic agents.

Keywords: Conformational changes; Enzymes; Active sites; Structure; Crystallography; Protein crystallization; Enzyme Inhibitors

¹ E-mail: zhihong.v.lai{at}gsk.com

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