title: c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty.
abstract: The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding.
authors.affiliation: Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
authors.forename: Bhushan
authors.initials: B
authors.lastname: Nagar
authors.forename: Filipp
authors.initials: F
authors.lastname: Frank
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Cao
authors.forename: M Nidanie
authors.initials: MN
authors.lastname: Henderson
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001549:Benzamides; D000081247:CSK Tyrosine-Protein Kinase; D002645:Chickens; D018360:Crystallography, X-Ray; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D019061:src-Family Kinases
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000081247:CSK Tyrosine-Protein Kinase; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; C000631346:CSK protein, human