title: A conserved protonation-dependent switch controls drug binding in the Abl kinase.
abstract: In many protein kinases, a characteristic conformational change (the "DFG flip") connects catalytically active and inactive conformations. Many kinase inhibitors--including the cancer drug imatinib--selectively target a specific DFG conformation, but the function and mechanism of the flip remain unclear. Using long molecular dynamics simulations of the Abl kinase, we visualized the DFG flip in atomic-level detail and formulated an energetic model predicting that protonation of the DFG aspartate controls the flip. Consistent with our model's predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence that disappears when the DFG aspartate is mutated. Our model suggests a possible explanation for the high degree of conservation of the DFG motif: that the flip, modulated by electrostatic changes inherent to the catalytic cycle, allows the kinase to access flexible conformations facilitating nucleotide binding and release.
authors.affiliation: D. E. Shaw Research, New York, NY 10036, USA.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
authors.forename: Michael P
authors.initials: MP
authors.lastname: Eastwood
authors.forename: Filipp
authors.initials: F
authors.lastname: Frank
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xu
authors.forename: Morten Ø
authors.initials: MØ
authors.lastname: Jensen
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
mesh_terms: D020816:Amino Acid Motifs; D001224:Aspartic Acid; D002384:Catalysis; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D004364:Pharmaceutical Preparations; D001224:Aspartic Acid; D016315:Proto-Oncogene Proteins c-abl