Publication

Article Metrics

Citations


Online attention

Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2

DOI: 10.1038/srep28528 DOI Help

Authors: Matej Janeček (MRC Cancer Unit, University of Cambridge; Department of Chemistry, University of Cambridge) , Maxim Rossmann (Department of Biochemistry, University of Cambridge, Diamond Light Source) , Pooja Sharma (MRC Cancer Unit, University of Cambridge) , Amy Emery (MRC Cancer Unit, University of Cambridge) , David J. Huggins (MRC Cancer Unit, University of Cambridge) , Simon R. Stockwell (MRC Cancer Unit, University of Cambridge) , Jamie E. Stokes (Department of Chemistry, University of Cambridge) , Yaw S. Tan (Department of Chemistry, University of Cambridge) , Estrella Guarino Almeida (MRC Cancer Unit, University of Cambridge) , Bryn Hardwick (MRC Cancer Unit, University of Cambridge) , Ana Narvaez (University of Cambridge) , Marko Hyvonen (University of Cambridge) , David R. Spring (Department of Chemistry, University of Cambridge) , Grahame J. Mckenzie (MRC Cancer Unit, University of Cambridge) , Ashok R. Venkitaraman (MRC Cancer Unit, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 6

State: Published (Approved)
Published: June 2016
Diamond Proposal Number(s): 9007

Open Access Open Access

Abstract: The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the ‘Y pocket’) that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: Proxima1 at the SOLEIL Synchrotron, Gif-sur-Yvette, France.

Discipline Tags:



Technical Tags: