PDBsum entry 4z9l

Transferase/inhibitor

PDB id: 4z9l

Contents

Protein chain

333 a.a.

Ligands

ANP

880

UNX ×3

Waters ×67

PDB id:

4z9l

Name:

Transferase/inhibitor

Title:

The structure of jnk3 in complex with an imidazole-pyrimidine inhibitor

Structure:

Mitogen-activated protein kinase 10. Chain: a. Fragment: unp residues 40-401. Synonym: mapk 10,map kinase p49 3f12,stress-activated protein kinase 1b,sapk1b,stress-activated protein kinase jnk3,c-jun n-terminal kinase 3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk10, jnk3, jnk3a, prkm10, sapk1b. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.201 R-free: 0.226

Authors:

G.Scapin,S.B.Patel,J.Lisnock,J.W.Becker,P.V.Lograsso,O.S.Smart, G.Bricogne

Key ref:

G.Scapin et al. (2003). The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity. Chem Biol, 10, 705-712. PubMed id: 12954329 DOI: 10.1016/S1074-5521(03)00159-5

Date:

10-Apr-15 Release date: 06-May-15

Supersedes:

1pmq

Protein chain

P53779  (MK10_HUMAN) -  Mitogen-activated protein kinase 10 from Homo sapiens

Seq: 464 a.a.

Struc: 333 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⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = ANP) matches with 81.25% similarity) + ADP + H(+)

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

reference

DOI no: 10.1016/S1074-5521(03)00159-5

Chem Biol 10:705-712 (2003)

PubMed id: 12954329

The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity.

G.Scapin, S.B.Patel, J.Lisnock, J.W.Becker, P.V.LoGrasso.

ABSTRACT

The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.

Selected figure(s)

Figure 1.
Figure 1. Schematic Representation of the ATP Binding Site in KinasesATP (in ball-and-sticks) interacts mainly with the linker/adenine binding region (1), the ribose binding region (2), and the phosphate binding region (3). The two hydrophobic regions I (4) and II (5) do not directly interact with ATP and contain residues that vary among kinases, thus providing possibilities for the development of selective inhibitors [17]. Figures 1, 2B, and 3–6 were made with RIBBONS [42].

Figure 5.
Figure 5. Binding of Compound 3 to JNK3(A) Overlay of the Cα traces of JNK3:compound 1 (magenta) and JNK3:compound 3 complexes (yellow) in the region of the glycine-rich loop (G71-V78). The conformational change observed for residues Ile70–Ile77 was ligand induced.(B) Close-up of the compound 3 binding site; hydrogen bond interactions with protein atoms are shown as blue dotted lines.

The above figures are reprinted by permission from Cell Press: Chem Biol (2003, 10, 705-712) copyright 2003.

Figures were selected by the author.