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PDBsum entry 2oza

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protein Protein-protein interface(s) links
Signaling protein/transferase PDB id
2oza
Jmol
Contents
Protein chains
332 a.a. *
340 a.a. *
Waters ×60
* Residue conservation analysis
PDB id:
2oza
Name: Signaling protein/transferase
Title: Structure of p38alpha complex
Structure: Map kinase-activated protein kinase 2. Chain: a. Fragment: mk2. Synonym: mapk-activated protein kinase 2. Mapkap kinase 2. Mapkapk-2. Mk2. Engineered: yes. Mitogen-activated protein kinase 14. Chain: b. Fragment: p38a.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mapkapk2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Mus musculus. House mouse. Organism_taxid: 10090.
Resolution:
2.70Å     R-factor:   0.239     R-free:   0.296
Authors: A.White,C.A.Pargellis,J.M.Studts,B.G.Werneburg,B.T.Farmer Ii
Key ref:
A.White et al. (2007). Molecular basis of MAPK-activated protein kinase 2:p38 assembly. Proc Natl Acad Sci U S A, 104, 6353-6358. PubMed id: 17395714 DOI: 10.1073/pnas.0701679104
Date:
25-Feb-07     Release date:   03-Apr-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P49137  (MAPK2_HUMAN) -  MAP kinase-activated protein kinase 2
Seq:
Struc:
400 a.a.
332 a.a.
Protein chain
Pfam   ArchSchema ?
P47811  (MK14_MOUSE) -  Mitogen-activated protein kinase 14
Seq:
Struc:
360 a.a.
340 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: Chain A: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
   Enzyme class 2: Chain B: E.C.2.7.11.24  - Mitogen-activated protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cell   7 terms 
  Biological process     intracellular signal transduction   40 terms 
  Biochemical function     nucleotide binding     10 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0701679104 Proc Natl Acad Sci U S A 104:6353-6358 (2007)
PubMed id: 17395714  
 
 
Molecular basis of MAPK-activated protein kinase 2:p38 assembly.
A.White, C.A.Pargellis, J.M.Studts, B.G.Werneburg, B.T.Farmer.
 
  ABSTRACT  
 
p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38alpha isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-A resolution crystal structure of the unphosphorylated complex between p38alpha and MK2. These protein kinases bind "head-to-head," present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366-Ala-390, which includes the bipartite nuclear localization signal, binds to the p38alpha-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38alpha binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38alpha active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38alpha and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Environment of the p38 (yellow and green) phosphorylation region interacting with MK2 (blue). (A) Intermolecular H bonds (black dashed line) in the vicinity of p38 Tyr-182 interaction with MK2. The intermolecular antiparallel plated -sheet formed by 10 and 10' is shown with two arrows. The MK2 region Ser-265'–Gln-283' (green) is flanked by Tyr-264' and Tyr-284', both of which are involved in intermolecular H bonds with p38 . The MK2 phosphorylation region around Ser-272' is unresolved and represented with the green dotted line. (B) The p38 phosphorylation lip Tyr-182 interacts in a MK2 surface pocket.
Figure 4.
Fig. 4. Heterodimer-induced conformational changes of MK2 and p38 . (A) Overlay of the uncomplexed p38 (orange) (36) with the p38 (blue) from MK2:p38 . Only the carbon– -chain trace is shown on this stereoview. Areas of significant differences (red) are annotated for the hinge region at and around Met-109 (H) and for the activation loop (A). (B) Overlay of the uncomplexed inactive MK2 (i-mk2) (gray) (20), the uncomplexed partially active MK2 (a-mk2) (light blue) (35), and the MK2 (green) from MK2:p38 . As in A, only the carbon– -trace is shown on this stereoview. The four noticeable conformational change regions (red) are annotated for the P loop (P), the regulatory phosphorylation region near Ser-272' ([*]), the activation loop (A), and the C-terminal docking region 370'–400' (#).
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20640477 S.Kostenko, M.T.Khan, I.Sylte, and U.Moens (2011).
The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor.
  Cell Mol Life Sci, 68, 289-301.  
21494553 S.Lee, M.Warthaka, C.Yan, T.S.Kaoud, A.Piserchio, R.Ghose, P.Ren, and K.N.Dalby (2011).
A model of a MAPK•substrate complex in an active conformation: a computational and experimental approach.
  PLoS One, 6, e18594.  
20626350 A.Cuadrado, and A.R.Nebreda (2010).
Mechanisms and functions of p38 MAPK signalling.
  Biochem J, 429, 403-417.  
20462950 K.Lee, A.E.Kenny, and C.L.Rieder (2010).
P38 mitogen-activated protein kinase activity is required during mitosis for timely satisfaction of the mitotic checkpoint but not for the fidelity of chromosome segregation.
  Mol Biol Cell, 21, 2150-2160.  
20833869 M.Ito, K.Miyado, K.Nakagawa, M.Muraki, M.Imai, N.Yamakawa, J.Qin, Y.Hosoi, H.Saito, and Y.Takahashi (2010).
Age-associated changes in the subcellular localization of phosphorylated p38 MAPK in human granulosa cells.
  Mol Hum Reprod, 16, 928-937.  
20506250 X.Gong, X.Ming, P.Deng, and Y.Jiang (2010).
Mechanisms regulating the nuclear translocation of p38 MAP kinase.
  J Cell Biochem, 110, 1420-1429.  
19706521 A.Bakan, and I.Bahar (2009).
The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding.
  Proc Natl Acad Sci U S A, 106, 14349-14354.  
19513107 E.Zeqiraj, B.M.Filippi, S.Goldie, I.Navratilova, J.Boudeau, M.Deak, D.R.Alessi, and D.M.van Aalten (2009).
ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor.
  PLoS Biol, 7, e1000126.
PDB code: 3gni
19230643 H.C.Reinhardt, and M.B.Yaffe (2009).
Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2.
  Curr Opin Cell Biol, 21, 245-255.  
19369945 J.Schwermann, C.Rathinam, M.Schubert, S.Schumacher, F.Noyan, H.Koseki, A.Kotlyarov, C.Klein, and M.Gaestel (2009).
MAPKAP kinase MK2 maintains self-renewal capacity of haematopoietic stem cells.
  EMBO J, 28, 1392-1406.  
19296855 M.A.Argiriadi, S.Sousa, D.Banach, D.Marcotte, T.Xiang, M.J.Tomlinson, M.Demers, C.Harris, S.Kwak, J.Hardman, M.Pietras, L.Quinn, J.DiMauro, B.Ni, J.Mankovich, D.W.Borhani, R.V.Talanian, and R.Sadhukhan (2009).
Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study.
  BMC Struct Biol, 9, 16.  
19622861 S.B.Patel, P.M.Cameron, S.J.O'Keefe, B.Frantz-Wattley, J.Thompson, E.A.O'Neill, T.Tennis, L.Liu, J.W.Becker, and G.Scapin (2009).
The three-dimensional structure of MAP kinase p38beta: different features of the ATP-binding site in p38beta compared with p38alpha.
  Acta Crystallogr D Biol Crystallogr, 65, 777-785.
PDB codes: 3gc7 3gc8 3gc9
19243309 T.Chen, N.Kablaoui, J.Little, S.Timofeevski, W.R.Tschantz, P.Chen, J.Feng, M.Charlton, R.Stanton, and P.Bauer (2009).
Identification of small-molecule inhibitors of the JIP-JNK interaction.
  Biochem J, 420, 283-294.  
19561096 T.Yoshizawa, D.Hammaker, D.L.Boyle, M.Corr, R.Flavell, R.Davis, G.Schett, and G.S.Firestein (2009).
Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression.
  J Immunol, 183, 1360-1367.  
18501927 K.M.Sours, S.C.Kwok, T.Rachidi, T.Lee, A.Ring, A.N.Hoofnagle, K.A.Resing, and N.G.Ahn (2008).
Hydrogen-exchange mass spectrometry reveals activation-induced changes in the conformational mobility of p38alpha MAP kinase.
  J Mol Biol, 379, 1075-1093.  
18620516 S.Duraisamy, M.Bajpai, U.Bughani, S.G.Dastidar, A.Ray, and P.Chopra (2008).
MK2: a novel molecular target for anti-inflammatory therapy.
  Expert Opin Ther Targets, 12, 921-936.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.