The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
A conserved protonation-dependent switch controls drug binding in the Abl kinase
Open accessAbstract
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.
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Cites
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Molecular dynamics---Scalable algorithms for molecular dynamics simulations on commodity clusters
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Self-citationStructural analysis of the catalytically inactive kinase domain of the human EGF receptor 3
Jura, N., Shan, Y., Cao, X., Shaw, D. E., & Kuriyan, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912101106 · Cited by 338
Self-citationActivation pathway of Src kinase reveals intermediate states as targets for drug design
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Catalytic Control in the EGF Receptor and Its Connection to General Kinase Regulatory Mechanisms
Jura, N., Zhang, X., Endres, N. F., Seeliger, M. A., Schindler, T., & Kuriyan, J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.004 · Cited by 310
Self-citationConformational states dynamically populated by a kinase determine its function
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Metadata
- Authors
- Shan, Y., Seeliger, M. A., Eastwood, M. P., Frank, F., Xu, H., Jensen, M. Ø., Dror, R. O., Kuriyan, J., & Shaw, D. E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-01-06
- Volume
- 106
- Issue
- 1
- Pages
- 139-144
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2079620307
- Cited by
- 262
- References
- 51
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- green
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