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

Janeček M, Rossmann M, Sharma P, Emery A, Huggins DJ, Stockwell SR, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvönen M, Spring DR, McKenzie GJ, Venkitaraman AR
Sci Rep 6 28528 (2016)
Related entries: 5dn3, 5dnr, 5dos, 5dr2, 5dr6, 5dr9, 5drd, 5dt0, 5dt3, 5dt4

Cited: 35 times
EuropePMC logo PMID: 27339427

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.

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Reviews citing this publication (12)

  1. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area. Ran X, Gestwicki JE. Curr Opin Chem Biol 44 75-86 (2018)
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Articles citing this publication (22)

  1. Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states. Lake EW, Muretta JM, Thompson AR, Rasmussen DM, Majumdar A, Faber EB, Ruff EF, Thomas DD, Levinson NM. Proc Natl Acad Sci U S A 115 E11894-E11903 (2018)
  2. Identification of five hub genes as monitoring biomarkers for breast cancer metastasis in silico. Cai Y, Mei J, Xiao Z, Xu B, Jiang X, Zhang Y, Zhu Y. Hereditas 156 20 (2019)
  3. Oxidative stress induces mitotic arrest by inhibiting Aurora A-involved mitotic spindle formation. Wang GF, Dong Q, Bai Y, Yuan J, Xu Q, Cao C, Liu X. Free Radic Biol Med 103 177-187 (2017)
  4. Allosteric modulation of a human protein kinase with monobodies. Zorba A, Nguyen V, Koide A, Hoemberger M, Zheng Y, Kutter S, Kim C, Koide S, Kern D. Proc Natl Acad Sci U S A 116 13937-13942 (2019)
  5. CRISPRO: identification of functional protein coding sequences based on genome editing dense mutagenesis. Schoonenberg VAC, Cole MA, Yao Q, Macias-Treviño C, Sher F, Schupp PG, Canver MC, Maeda T, Pinello L, Bauer DE. Genome Biol 19 169 (2018)
  6. Dynamics of human protein kinase Aurora A linked to drug selectivity. Pitsawong W, Buosi V, Otten R, Agafonov RV, Zorba A, Kern N, Kutter S, Kern G, Pádua RA, Meniche X, Kern D. Elife 7 e36656 (2018)
  7. A kinase-independent function for AURORA-A in replisome assembly during DNA replication initiation. Guarino Almeida E, Renaudin X, Venkitaraman AR. Nucleic Acids Res 48 7844-7855 (2020)
  8. Integrated Bioinformatic Analysis Identifies Networks and Promising Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma. Ji Y, Yin Y, Zhang W. Int J Genomics 2020 2061024 (2020)
  9. Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase. Zhang R, McIntyre PJ, Collins PM, Foley DJ, Arter C, von Delft F, Bayliss R, Warriner S, Nelson A. Chemistry 25 6831-6839 (2019)
  10. Development of a multipurpose scaffold for the display of peptide loops. Rossmann M, J Greive S, Moschetti T, Dinan M, Hyvönen M. Protein Eng Des Sel 30 419-430 (2017)
  11. Identification of small molecule inhibitors of the Aurora-A/TPX2 complex. Asteriti IA, Daidone F, Colotti G, Rinaldo S, Lavia P, Guarguaglini G, Paiardini A. Oncotarget 8 32117-32133 (2017)
  12. Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction. Cole DJ, Janecek M, Stokes JE, Rossmann M, Faver JC, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR, Huggins DJ, Jorgensen WL. Chem Commun (Camb) 53 9372-9375 (2017)
  13. Importin α phosphorylation promotes TPX2 activation by GM130 to control astral microtubules and spindle orientation. Guo H, Wei JH, Zhang Y, Seemann J. J Cell Sci 134 jcs258356 (2021)
  14. Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation. Gilburt JAH, Girvan P, Blagg J, Ying L, Dodson CA. Chem Sci 10 4069-4076 (2019)
  15. Selective α-Methylation of Aryl Ketones Using Quaternary Ammonium Salts as Solid Methylating Agents. Templ J, Schnürch M. J Org Chem 87 4305-4315 (2022)
  16. Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1. Huggins DJ, Hardwick BS, Sharma P, Emery A, Laraia L, Zhang F, Narvaez AJ, Roberts-Thomson M, Crooks AT, Boyle RG, Boyce R, Walker DW, Mateu N, McKenzie GJ, Spring DR, Venkitaraman AR. ACS Omega 5 822-831 (2020)
  17. The structural basis of the multi-step allosteric activation of Aurora B kinase. Segura-Peña D, Hovet O, Gogoi H, Dawicki-McKenna J, Hansen Wøien SM, Carrer M, Black BE, Cascella M, Sekulic N. Elife 12 e85328 (2023)
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  19. Comparative expression of soluble, active human kinases in specialized bacterial strains. Sunderhaus A, Imran R, Enoh E, Adedeji A, Obafemi T, Abdel Aziz MH. PLoS One 17 e0267226 (2022)
  20. Computational and Biophysical Characterization of Heterocyclic Derivatives of Anthraquinone against Human Aurora Kinase A. Singh M, Haque MA, Tikhomirov AS, Shchekotikhin AE, Das U, Kaur P. ACS Omega 7 39603-39618 (2022)
  21. Structural basis for CEP192-mediated regulation of centrosomal AURKA. Park JG, Jeon H, Shin S, Song C, Lee H, Kim NK, Kim EE, Hwang KY, Lee BJ, Lee IG. Sci Adv 9 eadf8582 (2023)
  22. TWN-FS method: A novel fragment screening method for drug discovery. Yoon HR, Park GJ, Balupuri A, Kang NS. Comput Struct Biotechnol J 21 4683-4696 (2023)


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