title: Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.
abstract: Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Agafonov
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hoemberger
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kutter
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zorba
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: J
authors.initials: J
authors.lastname: Halpin
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: V
authors.initials: V
authors.lastname: Buosi
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: R
authors.initials: R
authors.lastname: Otten
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: D
authors.initials: D
authors.lastname: Waterman
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Theobald
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. dkern@brandeis.edu.
authors.forename: D
authors.initials: D
authors.lastname: Kern
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019277:Entropy; D019143:Evolution, Molecular; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D016374:Oncogene Proteins v-abl / Q000737:chemistry / Q000235:genetics; D010802:Phylogeny; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D019061:src-Family Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016374:Oncogene Proteins v-abl; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019061:src-Family Kinases