title: Energetic dissection of Gleevec's selectivity toward human tyrosine kinases.
abstract: Protein kinases are obvious drug targets against cancer, owing to their central role in cellular regulation. Since the discovery of Gleevec, a potent and specific inhibitor of Abl kinase, as a highly successful cancer therapeutic, the ability of this drug to distinguish between Abl and other tyrosine kinases such as Src has been intensely investigated but without much success. Using NMR and fast kinetics, we establish a new model that solves this longstanding question of how the two tyrosine kinases adopt almost identical structures when bound to Gleevec but have vastly different affinities. We show that, in contrast to all other proposed models, the origin of Abl's high affinity lies predominantly in a conformational change after binding. An energy landscape providing tight affinity via an induced fit and binding plasticity via a conformational-selection mechanism is likely to be general for many inhibitors.
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA. [2].
authors.forename: Roman V
authors.initials: RV
authors.lastname: Agafonov
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA. [2].
authors.forename: Christopher
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Otten
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buosi
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kern
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D009369:Neoplasms / Q000201:enzymology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics; D019061:src-Family Kinases / Q000648:ultrastructure
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases