PDBsum entry 4zsg

Kinase

PDB id: 4zsg

Contents

Protein chain

347 a.a.

Ligands

GOL ×5

4QX

Waters ×344

PDB id:

4zsg

Name:

Kinase

Title:

Mitogen activated protein kinase 7 in complex with inhibitor

Structure:

Mitogen-activated protein kinase 7. Chain: a. Fragment: residues 47-393. Synonym: mapk 7,big map kinase 1,bmk-1,extracellular signal-regulated kinase 5,erk-5. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk7, bmk1, erk5, prkm7. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.79Å R-factor: 0.206 R-free: 0.235

Authors:

J.Tucker,D.J.Ogg

Key ref:

H.Chen et al. (2016). Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site. Acta Crystallogr D Struct Biol, 72, 682-693. PubMed id: 27139631 DOI: 10.1107/S2059798316004502

Date:

13-May-15 Release date: 04-May-16

Protein chain

Q13164  (MK07_HUMAN) -  Mitogen-activated protein kinase 7 from Homo sapiens

Seq: 816 a.a.

Struc: 347 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1107/S2059798316004502

Acta Crystallogr D Struct Biol 72:682-693 (2016)

PubMed id: 27139631

Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site.

H.Chen, J.Tucker, X.Wang, P.R.Gavine, C.Phillips, M.A.Augustin, P.Schreiner, S.Steinbacher, M.Preston, D.Ogg.

ABSTRACT

MAP kinases act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, regulation of transcription and development. As a member of the MAP kinase family, ERK5 (MAPK7) is involved in the downstream signalling pathways of various cell-surface receptors, including receptor tyrosine kinases and G protein-coupled receptors. In the current study, five structures of the ERK5 kinase domain co-crystallized with ERK5 inhibitors are reported. Interestingly, three of the compounds bind at a novel allosteric binding site in ERK5, while the other two bind at the typical ATP-binding site. Binding of inhibitors at the allosteric site is accompanied by displacement of the P-loop into the ATP-binding site and is shown to be ATP-competitive in an enzymatic assay of ERK5 kinase activity. Kinase selectivity data show that the most potent allosteric inhibitor exhibits superior kinase selectivity compared with the two inhibitors that bind at the canonical ATP-binding site. An analysis of these structures and comparison with both a previously published ERK5-inhibitor complex structure (PDB entry 4b99) and the structures of three other kinases (CDK2, ITK and MEK) in complex with allosteric inhibitors are presented.