Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase
The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2000-09, Vol.289 (5486), p.1938-1942 |
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| container_issue | 5486 |
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| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 289 |
| creator | Schindler, Thomas Bornmann, William Pellicena, Patricia Miller, W. Todd Clarkson, Bayard Kuriyan, John |
| description | The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity. |
| doi_str_mv | 10.1126/science.289.5486.1938 |
| format | Article |
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Myelofibrosis ; Literary Devices ; Medical sciences ; Mice ; Models, Molecular ; Molecular biology ; Molecular biophysics ; Molecules ; Phosphorylation ; Piperazines ; Protein Conformation ; Protein tyrosine kinase ; Proteins ; Proto-Oncogene Proteins c-abl - antagonists & inhibitors ; Proto-Oncogene Proteins c-abl - chemistry ; Proto-Oncogene Proteins c-abl - metabolism ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Receptors ; Recombinant Fusion Proteins ; Structure in molecular biology ; Structure-Activity Relationship</subject><ispartof>Science (American Association for the Advancement of Science), 2000-09, Vol.289 (5486), p.1938-1942</ispartof><rights>Copyright 2000 American Association for the Advancement of Science</rights><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2000 American Association for the Advancement of Science</rights><rights>COPYRIGHT 2000 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Sep 15, 2000</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c785t-8b2e3757def35b74f3163330f6d6e75195b01cebd40caca5b1229ad8f3680bdb3</citedby><cites>FETCH-LOGICAL-c785t-8b2e3757def35b74f3163330f6d6e75195b01cebd40caca5b1229ad8f3680bdb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3077690$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3077690$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,2870,2871,27903,27904,57995,58228</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=820085$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10988075$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schindler, Thomas</creatorcontrib><creatorcontrib>Bornmann, William</creatorcontrib><creatorcontrib>Pellicena, Patricia</creatorcontrib><creatorcontrib>Miller, W. Todd</creatorcontrib><creatorcontrib>Clarkson, Bayard</creatorcontrib><creatorcontrib>Kuriyan, John</creatorcontrib><title>Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.</description><subject>Abelson tyrosine kinase</subject><subject>Abl gene</subject><subject>Alleles</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Atoms</subject><subject>Benzamides</subject><subject>Biological and medical sciences</subject><subject>Catalytic Domain</subject><subject>Cells</subject><subject>Control loops</subject><subject>Crystalline structure</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Activation</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fundamental and applied biological sciences. 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Myelofibrosis</topic><topic>Literary Devices</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecular biology</topic><topic>Molecular biophysics</topic><topic>Molecules</topic><topic>Phosphorylation</topic><topic>Piperazines</topic><topic>Protein Conformation</topic><topic>Protein tyrosine kinase</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-abl - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-abl - chemistry</topic><topic>Proto-Oncogene Proteins c-abl - metabolism</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptors</topic><topic>Recombinant Fusion Proteins</topic><topic>Structure in molecular biology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schindler, Thomas</creatorcontrib><creatorcontrib>Bornmann, William</creatorcontrib><creatorcontrib>Pellicena, Patricia</creatorcontrib><creatorcontrib>Miller, W. 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| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2000-09, Vol.289 (5486), p.1938-1942 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743481834 |
| source | MEDLINE; American Association for the Advancement of Science; Jstor Complete Legacy |
| subjects | Abelson tyrosine kinase Abl gene Alleles Amino acids Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Atoms Benzamides Biological and medical sciences Catalytic Domain Cells Control loops Crystalline structure Crystallography Crystallography, X-Ray Enzyme Activation Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Fundamental and applied biological sciences. Psychology Hematologic and hematopoietic diseases Humans Hydrogen bonds Imatinib Mesylate Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Literary Devices Medical sciences Mice Models, Molecular Molecular biology Molecular biophysics Molecules Phosphorylation Piperazines Protein Conformation Protein tyrosine kinase Proteins Proto-Oncogene Proteins c-abl - antagonists & inhibitors Proto-Oncogene Proteins c-abl - chemistry Proto-Oncogene Proteins c-abl - metabolism Pyrimidines - chemistry Pyrimidines - pharmacology Receptors Recombinant Fusion Proteins Structure in molecular biology Structure-Activity Relationship |
| title | Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase |
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