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A conserved protonation-dependent switch controls drug binding in the Abl kinase
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Proceedings of the National Academy of Sciences, 106, 2009, 1, S. 139-144 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. |
|---|---|
| author |
Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. |
| spellingShingle |
Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. Proceedings of the National Academy of Sciences A conserved protonation-dependent switch controls drug binding in the Abl kinase Multidisciplinary |
| author_sort |
shan, yibing |
| spelling |
Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0811223106 <jats:p>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.</jats:p> A conserved protonation-dependent switch controls drug binding in the Abl kinase Proceedings of the National Academy of Sciences |
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| title |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_unstemmed |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_full |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_fullStr |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_full_unstemmed |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_short |
A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_sort |
a conserved protonation-dependent switch controls drug binding in the abl kinase |
| topic |
Multidisciplinary |
| url |
http://dx.doi.org/10.1073/pnas.0811223106 |
| publishDate |
2009 |
| physical |
139-144 |
| description |
<jats:p>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.</jats:p> |
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| author | Shan, Yibing, Seeliger, Markus A., Eastwood, Michael P., Frank, Filipp, Xu, Huafeng, Jensen, Morten Ø, Dror, Ron O., Kuriyan, John, Shaw, David E. |
| author_facet | Shan, Yibing, Seeliger, Markus A., Eastwood, Michael P., Frank, Filipp, Xu, Huafeng, Jensen, Morten Ø, Dror, Ron O., Kuriyan, John, Shaw, David E., Shan, Yibing, Seeliger, Markus A., Eastwood, Michael P., Frank, Filipp, Xu, Huafeng, Jensen, Morten Ø, Dror, Ron O., Kuriyan, John, Shaw, David E. |
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| description | <jats:p>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.</jats:p> |
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| spelling | Shan, Yibing Seeliger, Markus A. Eastwood, Michael P. Frank, Filipp Xu, Huafeng Jensen, Morten Ø Dror, Ron O. Kuriyan, John Shaw, David E. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.0811223106 <jats:p>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.</jats:p> A conserved protonation-dependent switch controls drug binding in the Abl kinase Proceedings of the National Academy of Sciences |
| spellingShingle | Shan, Yibing, Seeliger, Markus A., Eastwood, Michael P., Frank, Filipp, Xu, Huafeng, Jensen, Morten Ø, Dror, Ron O., Kuriyan, John, Shaw, David E., Proceedings of the National Academy of Sciences, A conserved protonation-dependent switch controls drug binding in the Abl kinase, Multidisciplinary |
| title | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_full | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_fullStr | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_full_unstemmed | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_short | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| title_sort | a conserved protonation-dependent switch controls drug binding in the abl kinase |
| title_unstemmed | A conserved protonation-dependent switch controls drug binding in the Abl kinase |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.0811223106 |