PDBsum entry 3hvc

Transferase

PDB id: 3hvc

Contents

Protein chain

327 a.a. *

Ligands

GG5 ×2

Waters ×193

* Residue conservation analysis

PDB id:

3hvc

Name:

Transferase

Title:

Crystal structure of human p38alpha map kinase

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csbp, csbp1, csbp2, cspb1, mapk14, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.226 R-free: 0.267

Authors:

J.J.Perry,J.A.Tainer

Key ref:

J.J.Perry et al. (2009). p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses. J Mol Biol, 391, 1. PubMed id: 19501598 DOI: 10.1016/j.jmb.2009.06.005

Date:

15-Jun-09 Release date: 30-Jun-09

Supersedes:

2p5a

Protein chain

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

Seq: 360 a.a.

Struc: 327 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: 10.1016/j.jmb.2009.06.005

J Mol Biol 391:1 (2009)

PubMed id: 19501598

p38alpha MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses.

J.J.Perry, R.M.Harris, D.Moiani, A.J.Olson, J.A.Tainer.

ABSTRACT

The mitogen-activated protein (MAP) kinase protein family has a critical role in cellular signaling events, with MAP kinase p38alpha acting in inflammatory processes and being an important drug discovery target. MAP kinase drug design efforts have focused on small-molecule inhibitors of the ATP catalytic site, which exhibit dose-limiting adverse effects. Therefore, characterizing other potential sites that bind substrates, inhibitors, or allosteric effectors is of great interest. Here, we present the crystal structure of human p38alpha MAP kinase, which has a lead compound bound both in the active site and in the lipid-binding site of the C-terminal cap. This C-terminal cap is formed from an extension to the kinase fold, unique to the MAP kinase and cyclin-dependent kinase families and glycogen synthase kinase 3. Binding of this lead, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine, to wild-type p38alpha induces movement of the C-terminal cap region, creating a hydrophobic pocket centered around residue Trp197. Computational analysis of this C-terminal domain pocket indicates notable flexibility for potentially binding different-shaped compounds, including lipids, oxidized arachidonic acid species such as leukotrienes, and small-molecule effectors. Furthermore, our structural results defining the open p38alpha C-lobe pocket provide a detailed framework for the design of novel small molecules with affinities comparable to active-site binders: to bind and potentially modulate the shape and activity of p38alpha in predetermined ways. Moreover, these results and analyses of p38alpha suggest strategies for designing specific binding compounds applicable to other MAP kinases, as well as the cyclin-dependent kinase family and glycogen synthase kinase 3beta that also utilize the C-terminal insert in their interactions.

Selected figure(s)

Figure 1.
Fig. 1. The molecular structures of (a) 4-FPP and (b) SB203580.

Figure 2.
Fig. 2. The p38α MAP kinase:4-FPP complex crystal structure. (a) The p38α MAP kinase:4-FPP complex structure, with secondary structural elements in green and surface in transparent gray. Two 4-FPP molecules, depicted as spheres, are bound to p38α. One molecule is bound at the active site and is shown in magenta, and the second binds to the C-terminal domain MAP kinase hydrophobic pocket, depicted in salmon. (b) Interactions of 4-FPP in the active-site pocket (the surface of p38α is depicted in transparent gray). 4-FPP forms a 2.7 Å hydrogen bond with the Met109 main-chain nitrogen, and the pyrazol group forms a hydrogen bond with a water molecule that also forms hydrogen bonds with the Asp168 (of the ‘DFG’ loop) and Lys53 side chains (hydrogen bonds are depicted as yellow broken lines, and distances are expressed in angstroms).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 391, 1) copyright 2009.

Figures were selected by an automated process.