4QTA
Structure of human ERK2 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket
Summary for 4QTA
| Entry DOI | 10.2210/pdb4qta/pdb |
| Related | 4QTB 4QTC 4QTD 4QTE |
| Descriptor | Mitogen-activated protein kinase 1, 1,2-ETHANEDIOL, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | structural genomics, structural genomics consortium, sgc, transferase, kinase, mapk, signalling, inhibitor, allosteric, structural genomics consortium (sgc), transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm, cytoskeleton, spindle (By similarity): P28482 |
| Total number of polymer chains | 1 |
| Total formula weight | 42808.07 |
| Authors | Chaikuad, A.,Savitsky, P.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2014-07-07, release date: 2014-07-23, Last modification date: 2023-09-20) |
| Primary citation | Chaikuad, A.,M C Tacconi, E.,Zimmer, J.,Liang, Y.,Gray, N.S.,Tarsounas, M.,Knapp, S. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nat.Chem.Biol., 10:853-860, 2014 Cited by PubMed 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. PubMed: 25195011DOI: 10.1038/nchembio.1629 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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