5DR2

Aurora A Kinase in Complex with AA30 and ATP in Space Group P6122

Summary for 5DR2

• Entry DOI: 10.2210/pdb5dr2/pdb
• Descriptor: Aurora kinase A, 2-(3-bromophenyl)quinoline-4-carboxylic acid, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: aurora a kinase, mitotic kinase, ppi, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32667.17

Authors

Janecek, M.,Rossmann, M.,Sharma, P.,Emery, A.,McKenzie, G.J.,Huggins, D.J.,Stockwell, S.,Stokes, J.A.,Almeida, E.G.,Hardwick, B.,Narvaez, A.J.,Hyvonen, M.,Spring, D.R.,Venkitaraman, A.R. (deposition date: 2015-09-15, release date: 2016-07-20, Last modification date: 2024-01-10)

Primary citation

Janecek, M.,Rossmann, M.,Sharma, P.,Emery, A.,Huggins, D.J.,Stockwell, S.R.,Stokes, J.E.,Tan, Y.S.,Almeida, E.G.,Hardwick, B.,Narvaez, A.J.,Hyvonen, M.,Spring, D.R.,McKenzie, G.J.,Venkitaraman, A.R.
Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.
Sci Rep, 6:28528-28528, 2016

PubMed 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.

PubMed: 27339427
DOI: 10.1038/srep28528

Experimental method

X-RAY DIFFRACTION (2.46 Å)