5G1X

Crystal structure of Aurora-A kinase in complex with N-Myc

Summary for 5G1X

• Entry DOI: 10.2210/pdb5g1x/pdb
• Descriptor: AURORA KINASE A, N-MYC PROTO-ONCOGENE PROTEIN, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: transferase, aurora, aurora-a, kinase, n-myc, myc, neuroblastoma
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965; Nucleus: P04198
• Total number of polymer chains: 2
• Total formula weight: 40618.23

Authors

Richards, M.W.,Burgess, S.G.,Bayliss, R. (deposition date: 2016-03-31, release date: 2016-11-16, Last modification date: 2024-10-16)

Primary citation

Richards, M.,Burgess, S.,Poon, E.,Carstensen, A.,Eilers, M.,Chesler, L.,Bayliss, R.
Structural Basis of N-Myc Binding by Aurora-A and its Destabilization by Kinase Inhibitors
Proc.Natl.Acad.Sci.USA, 113:13726-, 2016

PubMed Abstract: Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCF However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCF We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCF to disfavor the generation of Lys48-linked polyubiquitin chains.

PubMed: 27837025
DOI: 10.1073/PNAS.1610626113

Experimental method

X-RAY DIFFRACTION (1.72 Å)