4QTD

Structure of human JNK1 in complex with SCH772984 and the AMPPNP-hydrolysed triphosphate revealing the second type-I binding mode

Summary for 4QTD

• Entry DOI: 10.2210/pdb4qtd/pdb
• Related: 4QTA 4QTB 4QTC 4QTE
• Descriptor: Mitogen-activated protein kinase 8, 1,2-ETHANEDIOL, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (7 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: P45983
• Total number of polymer chains: 1
• Total formula weight: 44776.68

Authors

Chaikuad, A.,Keates, T.,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

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: 25195011
DOI: 10.1038/nchembio.1629

Experimental method

X-RAY DIFFRACTION (1.5 Å)