title: A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.
abstract: Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: Telomere and Genome Stability Group, The Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford, UK.
authors.forename: Eliana M C
authors.initials: EM
authors.lastname: Tacconi
authors.affiliation: Telomere and Genome Stability Group, The Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford, UK.
authors.forename: Jutta
authors.initials: J
authors.lastname: Zimmer
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Nathanael S
authors.identifier: 0000000153547403
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Telomere and Genome Stability Group, The Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Oxford, UK.
authors.forename: Madalena
authors.initials: M
authors.lastname: Tarsounas
authors.affiliation: 1] Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK. [2] Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, USA. [3] Target Discovery Institute, University of Oxford, Nuffield Department of Medicine Research Building, Oxford, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011994:Recombinant Proteins; C587178:SCH772984; C530656:HASPIN protein, human; D017346:Protein Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8