title: NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.
abstract: Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type of allosteric inhibitors targeting the Abl myristoyl pocket was shown in preclinical studies to overcome ATP-site inhibitor resistance arising in some patients. Using NMR and small-angle X-ray scattering, we have analyzed the solution conformations of apo Abelson tyrosine kinase (c-Abl) and c-Abl complexes with ATP-site and allosteric inhibitors. Binding of the ATP-site inhibitor imatinib leads to an unexpected open conformation of the multidomain SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on Bcr-Abl. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed, inactivated state. Our data provide detailed insights on the poorly understood combined effect of the two inhibitor types, which is able to overcome drug resistance.
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Skora
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
authors.forename: Stephan
authors.initials: S
authors.lastname: Grzesiek
mesh_terms: D000494:Allosteric Regulation; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism; D002247:Carbon Isotopes / Q000032:analysis; D004926:Escherichia coli; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000737:chemistry*; D009587:Nitrogen Isotopes / Q000032:analysis; D019906:Nuclear Magnetic Resonance, Biomolecular; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D053838:Scattering, Small Angle
chemical_list: D001549:Benzamides; D002247:Carbon Isotopes; D046912:Multiprotein Complexes; D009587:Nitrogen Isotopes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl
keywords: CML; heteronuclear NMR; protein dynamics