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A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain
The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specifi...
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2006
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1450098/ https://www.ncbi.nlm.nih.gov/pubmed/16640460 http://dx.doi.org/10.1371/journal.pbio.0040144 |
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author | Levinson, Nicholas M Kuchment, Olga Shen, Kui Young, Matthew A Koldobskiy, Michael Karplus, Martin Cole, Philip A Kuriyan, John |
author_facet | Levinson, Nicholas M Kuchment, Olga Shen, Kui Young, Matthew A Koldobskiy, Michael Karplus, Martin Cole, Philip A Kuriyan, John |
author_sort | Levinson, Nicholas M |
collection | PubMed |
description | The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP–peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR–Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain. |
format | Text |
id | pubmed-1450098 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-14500982006-05-16 A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain Levinson, Nicholas M Kuchment, Olga Shen, Kui Young, Matthew A Koldobskiy, Michael Karplus, Martin Cole, Philip A Kuriyan, John PLoS Biol Research Article The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180° with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP–peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR–Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain. Public Library of Science 2006-05 2006-05-02 /pmc/articles/PMC1450098/ /pubmed/16640460 http://dx.doi.org/10.1371/journal.pbio.0040144 Text en Copyright: © 2006 Levinson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Levinson, Nicholas M Kuchment, Olga Shen, Kui Young, Matthew A Koldobskiy, Michael Karplus, Martin Cole, Philip A Kuriyan, John A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title | A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title_full | A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title_fullStr | A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title_full_unstemmed | A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title_short | A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain |
title_sort | src-like inactive conformation in the abl tyrosine kinase domain |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1450098/ https://www.ncbi.nlm.nih.gov/pubmed/16640460 http://dx.doi.org/10.1371/journal.pbio.0040144 |
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