Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2 - PubMed (original) (raw)

Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2

Baoguang Zhao et al. Protein Sci. 2008 Oct.

Abstract

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 cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a pi-pi 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 multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.

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Figures

Figure 1.

Figure 1.

A ribbon diagram of AurA kinase domain in complex with TPX2 and VX-680, colored by secondary structure. VX-680 is shown in a ball-and-stick presentation: yellow for carbon, orange for sulfur, red for oxygen, and blue for nitrogen atoms. The phosphorylated Thr288AUR residue is also shown in the ball-and-stick presentation.

Figure 2.

Figure 2.

Binding of VX-680 in the active site of AurA/TPX2. (A) The electron density of VX-680 contoured at 1.5σ from the final 2fo-fc map. The AurA carbons are shown in green, inhibitor carbons in yellow, oxygens in red, nitrogens in blue, sulfur in orange, and water molecules in light blue. (B) Interactions of VX-680 with the active site of AurA when TPX2 is bound. The backbone tracing is in gray and hydrogen bonds are shown as dotted black lines. (C) Interactions of VX-680 with the active site of AurA without TPX2 bound (adapted from Cheetham et al. 2007 and reprinted with permission from Elsevier ©2007).

Figure 3.

Figure 3.

Superposition of the backbones of AurA/TPX2/VX-680 (gold) and AurA/TPX2/ADP (gray, pdb: 1ol5) structures focusing on the different conformations of the glycine-rich loop. The Cα of Phe144AUR in the AurA/TPX2/VX-680 structure has moved by >8 Å. The VX-680 carbons are in yellow, the ADP carbons in green, oxygens in red, nitrogens in blue, sulfur and phosphorus in orange. The side chain of Phe144 is shown in stick form.

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References

    1. Anderson, K., Yang, J., Koretke, K., Nurse, K., Calamari, A., Kirkpatrick, R.B., Patrick, D., Silva, D., Tummino, P.J., Copeland, R.A., et al. Binding of TPX2 to Aurora A alters substrate and inhibitor interactions. Biochemistry. 2007;46:10287–10295. - PubMed
    1. Andrews, P.D. Aurora kinases: Shining lights on the therapeutic horizon? Oncogene. 2005;24:5005–5015. - PubMed
    1. Bayliss, R., Sardon, T., Vernos, I., Conti, E. Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol. Cell. 2003;12:851–862. - PubMed
    1. Bayliss, R., Sardon, T., Ebert, J., Lindner, D., Vernos, I., Conti, E. Determinants for Aurora-A activation and Aurora-B discrimination by TPX2. Cell Cycle. 2004;3:404–407. - PubMed
    1. Bischoff, J.R., Anderson, L., Zhu, Y., Mossie, K., Ng, L., Souza, B., Schryver, B., Flanagan, P., Clairvoyant, F., Ginther, C., et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–3065. - PMC - PubMed

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