Crystal structures of the staurosporine complexes provide a basis for developing highly selective MAP2K4 and MAP2K6 inhibitors.
Mayu KITANO *1, Seigo YUMURA1, Ruri MIHATA2, Kenkichi BABA1, Masaaki SAWA3,
Shigenori TANAKA4, Kaori FUKUZAWA2, Takayoshi KINOSHITA1
1Graduate School of Science, Osaka Metropolitan University
2Graduate School of Pharmaceutical Sciences, The University of Osaka
3Carna Biosciences, Inc.
4Molecular Photoscience Research Center, Kobe University
Human protein kinases are vital for maintaining biological functions and dysfunction of a kinase causes severe diseases. Selectivity against the drug-target kinase is pivotal in developing kinase inhibitors. The ATP-binding site is highly conserved among all kinases. Therefore, it is difficult to design specific inhibitors based only on the structures of the target kinase. In this study, we planned to clarify the structural insights for producing MAP2K selective inhibitors based upon crystal structures of on- and off-target kinases. Here, we tried to clarify the structural determinants for the discrepancy in activity of STU between MAP2K4 and MAP2K6. The crystal structure of the MAP2K6/STU complex was newly solved at 2.5 Å resolution by the PHENIX program suite and compared with that of the MAP2K4/STU complex at 2.95 Å resolution (unpublished data). Fragment molecular orbital (FMO) calculations were carried out to precisely analyze the interaction in the MAP2K6/STU and MAP2K4/STU complexes. Superimposition of the crystal structures of the MAP2K6/STU and MAP2K4/STU complexes underpinned the discrepancy in STU activity for MAP2K6 and MAP2K4 (IC50 values are 0.19 and 94 nM, respectively). STU in the MAP2K4 complex shifted forward the solvent region compared with in the MAP2K6 complex. This shift in the MAP2K4 complex decreased the number of hydrogen bonds compared with that in the MAP2K6 complex. Inter fragment interaction energy (IFIE) based upon the FMO calculations supported this structure-selectivity relationship.