PDBsum entry 4r3c

Transferase/transferase inhibitor

PDB id: 4r3c

Contents

Protein chain

336 a.a.

Ligands

GG5

3GF ×2

Metals

_CL

Waters ×153

PDB id:

4r3c

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of p38 alpha map kinase in complex with a novel isoform selective drug candidate

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: map kinase 14, mapk 14, cytokine suppressive anti- inflammatory drug-binding protein, csaid-binding protein, csbp, map kinase mxi2, max-interacting protein 2, mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, stress-activated protein kinase 2a, sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2, sapk2a. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.06Å R-factor: 0.178 R-free: 0.217

Authors:

V.L.Grum-Tokars,G.Minasov,S.M.Roy,W.F.Anderson,D.M.Watterson

Key ref:

S.M.Roy et al. (2015). Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. Acs Chem Neurosci, 6, 666-680. PubMed id: 25676389 DOI: 10.1021/acschemneuro.5b00002

Date:

14-Aug-14 Release date: 25-Feb-15

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 336 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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: 10.1021/acschemneuro.5b00002

Acs Chem Neurosci 6:666-680 (2015)

PubMed id: 25676389

Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.

S.M.Roy, V.L.Grum-Tokars, J.P.Schavocky, F.Saeed, A.Staniszewski, A.F.Teich, O.Arancio, A.D.Bachstetter, S.J.Webster, L.J.Van Eldik, G.Minasov, W.F.Anderson, J.C.Pelletier, D.M.Watterson.

ABSTRACT

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.