PDBsum entry 2jbp

Transferase

PDB id: 2jbp

Contents

Protein chains

(+ 3 more) 283 a.a. *

225 a.a. *

265 a.a. *

Ligands

P4O ×11

Waters ×18

* Residue conservation analysis

PDB id:

2jbp

Name:

Transferase

Title:

Protein kinase mk2 in complex with an inhibitor (crystal form-2, co- crystallization)

Structure:

Map kinase-activated protein kinase 2. Chain: a, b, c, d, e, f, g, h, i, j, k, l. Fragment: kinase domain, residues 41-364. Synonym: mapkap kinase 2, mapk-activated protein kinase 2, mapkapk-2, mk2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

3.31Å R-factor: 0.215 R-free: 0.279

Authors:

R.C.Hillig,U.Eberspaecher,F.Monteclaro,M.Huber,D.Nguyen,A.Mengel, B.Muller-Tiemann,U.Egner

Key ref:

R.C.Hillig et al. (2007). Structural basis for a high affinity inhibitor bound to protein kinase MK2. J Mol Biol, 369, 735-745. PubMed id: 17449059 DOI: 10.1016/j.jmb.2007.03.004

Date:

09-Dec-06 Release date: 20-Mar-07

Protein chains

P49137  (MAPK2_HUMAN) -  MAP kinase-activated protein kinase 2 from Homo sapiens

Seq: 400 a.a.

Struc: 283 a.a.

Protein chain

P49137  (MAPK2_HUMAN) -  MAP kinase-activated protein kinase 2 from Homo sapiens

Seq: 400 a.a.

Struc: 225 a.a.

Protein chains

P49137  (MAPK2_HUMAN) -  MAP kinase-activated protein kinase 2 from Homo sapiens

Seq: 400 a.a.

Struc: 265 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L: E.C.2.7.11.1 - non-specific serine/threonine 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.2007.03.004

J Mol Biol 369:735-745 (2007)

PubMed id: 17449059

Structural basis for a high affinity inhibitor bound to protein kinase MK2.

R.C.Hillig, U.Eberspaecher, F.Monteclaro, M.Huber, D.Nguyen, A.Mengel, B.Muller-Tiemann, U.Egner.

ABSTRACT

The Ser/Thr protein kinase MAPKAP kinase 2 (MK2) plays a crucial role in inflammation. We determined the structure of the kinase domain of MK2 in complex with a low molecular mass inhibitor in two different crystal forms, obtained from soaking and co-crystallization. To our knowledge, these are the first structures of MK2 showing the binding mode of an inhibitor with high binding affinity (IC50 8.5 nM). The two crystal forms revealed conformational flexibility in the binding site and extend the experimental basis for rational drug design. Crystal form-1 contained one MK2 molecule per asymmetric unit. Form-2 contained 12 molecules, which arrange into two different types of MK2 trimers. One of them may serve as a model for an intermediate state during substrate phosphorylation, as each MK2 monomer places its activation segment into the substrate peptide binding groove of the trimer neighbor.

Selected figure(s)

Figure 2.
Figure 2. MK2 crystal forms and electron density for compound-1. MK2 crystals and 2F[o]–F[c] electron density maps (contoured at 1.3 σ) for the inhibitor, in (a) for the cubic crystal form-1, in (b) for the orthorhombic crystal form-2 (molecule A). Despite the low resolution, the ligand could be placed unequivocally in both crystal forms.

Figure 4.
Figure 4. Stereo representation of compound-1 bound to the ATP-binding site of MK2. Inhibitor and interacting residues shown in stick representation and atom colors (inhibitor carbon atoms in green). In (a) crystal form-1, in (b) molecule-A of crystal form-2. Black dotted lines represent hydrogen bonds. Thick orange dotted lines indicate π–π stacking between compound-1 and Asp142, and two weak hydrogen bonds (C-H···O to Glu139 in (a) and (b) and N-H···π to Asp207 in (b)).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 369, 735-745) copyright 2007.

Figures were selected by an automated process.