6CPE

Structure of apo, dephosphorylated Aurora A (122-403) in an active conformation

Summary for 6CPE

• Entry DOI: 10.2210/pdb6cpe/pdb
• Descriptor: Aurora kinase A, 1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE (3 entities in total)
• Functional Keywords: protein kinase, dfg-loop, transferase, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33152.98

Authors

Otten, R.,Kutter, S.,Buosi, V.,Padua, R.A.P.,Kern, D. (deposition date: 2018-03-13, release date: 2018-06-27, Last modification date: 2023-10-04)

Primary citation

Pitsawong, W.,Buosi, V.,Otten, R.,Agafonov, R.V.,Zorba, A.,Kern, N.,Kutter, S.,Kern, G.,Padua, R.A.,Meniche, X.,Kern, D.
Dynamics of human protein kinase Aurora A linked to drug selectivity.
Elife, 7:-, 2018

PubMed Abstract: Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinase Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.

PubMed: 29901437
DOI: 10.7554/eLife.36656

Experimental method

X-RAY DIFFRACTION (2.45 Å)