PDBsum entry 3brt

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protein Protein-protein interface(s) links
Transferase/transcription PDB id
Protein chains
39 a.a. *
61 a.a. *
43 a.a. *
Waters ×62
* Residue conservation analysis
PDB id:
Name: Transferase/transcription
Title: Nemo/ikk association domain structure
Structure: Inhibitor of nuclear factor kappa-b kinase subunit beta,inhibitor of nuclear factor kappa-b kinase subunit alpha. Chain: a, c. Fragment: fusion protein consists of unp residues 701-730 of ikk-b and nemo-binding domain of ikk-a. Synonym: i-kappa-b-kinase beta, ikbkb, ikk-beta, ikk-b, i- kappa-b kinase 2, ikk2, nuclear factor nf-kappa-b inhibitor kinase beta, nfkbikb,i kappa-b kinase alpha,
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ikbkb, ikkb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: ikbkg, fip3, nemo
2.25Å     R-factor:   0.240     R-free:   0.282
Authors: L.F.Silvian
Key ref:
M.Rushe et al. (2008). Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure, 16, 798-808. PubMed id: 18462684 DOI: 10.1016/j.str.2008.02.012
21-Dec-07     Release date:   22-Apr-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O14920  (IKKB_HUMAN) -  Inhibitor of nuclear factor kappa-B kinase subunit beta
756 a.a.
39 a.a.*
Protein chain
Pfam   ArchSchema ?
O15111  (IKKA_HUMAN) -  Inhibitor of nuclear factor kappa-B kinase subunit alpha
745 a.a.
39 a.a.*
Protein chains
Pfam   ArchSchema ?
Q9Y6K9  (NEMO_HUMAN) -  NF-kappa-B essential modulator
419 a.a.
61 a.a.
Protein chain
Pfam   ArchSchema ?
O14920  (IKKB_HUMAN) -  Inhibitor of nuclear factor kappa-B kinase subunit beta
756 a.a.
43 a.a.*
Protein chain
Pfam   ArchSchema ?
O15111  (IKKA_HUMAN) -  Inhibitor of nuclear factor kappa-B kinase subunit alpha
745 a.a.
43 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 54 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.  - I-kappa-B kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + [I-kappa-B protein] = ADP + [I-kappa-B phosphoprotein]
+ [I-kappa-B protein]
+ [I-kappa-B phosphoprotein]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     IkappaB kinase activity     1 term  


    Added reference    
DOI no: 10.1016/j.str.2008.02.012 Structure 16:798-808 (2008)
PubMed id: 18462684  
Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site.
M.Rushe, L.Silvian, S.Bixler, L.L.Chen, A.Cheung, S.Bowes, H.Cuervo, S.Berkowitz, T.Zheng, K.Guckian, M.Pellegrini, A.Lugovskoy.
The phosphorylation of IkappaB by the IKK complex targets it for degradation and releases NF-kappaB for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKKalpha/beta kinases and a regulatory protein, NF-kappaB essential modulator (NEMO; IKKgamma). NEMO associates with the unphosphorylated IKK kinase C termini and activates the IKK complex's catalytic activity. However, detailed structural information about the NEMO/IKK interaction is lacking. In this study, we have identified the minimal requirements for NEMO and IKK kinase association using a variety of biophysical techniques and have solved two crystal structures of the minimal NEMO/IKK kinase associating domains. We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent.
  Selected figure(s)  
Figure 4.
Figure 4. The NEMO/IKKβ Peptide Complex Is an Asymmetrical, Parallel Four-Helix Bundle
(A) Overall structure of the complex. NEMO chains (B and D; pink and green) form binding site for linker and NBD of IKK chains (A and C; blue and yellow). The box indicates the major site for IKK interaction.
(B) NEMO dimer showing the hole that results from stripping away IKK peptides.
(C) Close-up view of the IKK binding site with the three hydrophobic residues (734, 739, and 741) of IKK in sticks (blue and yellow) and NEMO residues that form the IKK-binding site (green surface).
(D) Close-up view of the NEMO dimerization patches at the C-terminal regions of the helix.
(E) Close-up view of the NEMO dimerization patches at the N-terminal regions of the helix.
Figure 5.
Figure 5. The Linker and NBD of IKKα and IKKβ Bind in a Hydrophobic Cleft
(A) Sequences of the linker and NBD for IKKα and IKKβ.
(B) Surface representation of NEMO with the superimposed NBD and linker segments of the IKKα/β hybrid peptide (magenta) and the IKKβ peptide (green). The surface is colored yellow for hydrophobic surfaces, red for negatively charged surfaces, and blue for positively charged surfaces. Note that three hydrophobic residues (734, 739, and 741) fit in the hydrophobic cleft. There is a similar hydrogen bond between E89 of NEMO and the 734 backbone amide of each IKK peptide.
(C) Intramolecular hydrogen bonding of the linker and NBD of the IKK peptide, which constrains the unique, unwound conformation. Included is a cartoon of the three hydrophobic pockets and the H-bond from Glu89 to the backbone of the IKK linker region, which defines the pharmacaphores of this binding site.
  The above figures are reprinted by permission from Cell Press: Structure (2008, 16, 798-808) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21135870 C.Zheng, Q.Yin, and H.Wu (2011).
Structural studies of NF-κB signaling.
  Cell Res, 21, 183-195.  
21423167 G.Xu, Y.C.Lo, Q.Li, G.Napolitano, X.Wu, X.Jiang, M.Dreano, M.Karin, and H.Wu (2011).
Crystal structure of inhibitor of κB kinase β.
  Nature, 472, 325-330.
PDB codes: 3qa8 3qad 3rzf
21187855 S.Miyamoto (2011).
Nuclear initiated NF-κB signaling: NEMO and ATM take center stage.
  Cell Res, 21, 116-130.  
21143809 A.Grover, A.Shandilya, A.Punetha, V.S.Bisaria, and D.Sundar (2010).
Inhibition of the NEMO/IKKβ association complex formation, a novel mechanism associated with the NF-κB activation suppression by Withania somnifera's key metabolite withaferin A.
  BMC Genomics, 11, S25.  
  20300203 A.Israël (2010).
The IKK complex, a central regulator of NF-kappaB activation.
  Cold Spring Harb Perspect Biol, 2, a000158.  
20167598 E.T.Baima, J.A.Guzova, S.Mathialagan, E.E.Nagiec, M.M.Hardy, L.R.Song, S.L.Bonar, R.A.Weinberg, S.R.Selness, S.S.Woodard, J.Chrencik, W.F.Hood, J.F.Schindler, N.Kishore, and G.Mbalaviele (2010).
Novel insights into the cellular mechanisms of the anti-inflammatory effects of NF-kappaB essential modulator binding domain peptides.
  J Biol Chem, 285, 13498-13506.  
19763089 E.Laplantine, E.Fontan, J.Chiaravalli, T.Lopez, G.Lakisic, M.Véron, F.Agou, and A.Israël (2009).
NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain.
  EMBO J, 28, 2885-2895.  
19422324 F.J.Ivins, M.G.Montgomery, S.J.Smith, A.C.Morris-Davies, I.A.Taylor, and K.Rittinger (2009).
NEMO oligomerization and its ubiquitin-binding properties.
  Biochem J, 421, 243-251.  
19543231 K.Iwai, and F.Tokunaga (2009).
Linear polyubiquitination: a new regulator of NF-kappaB activation.
  EMBO Rep, 10, 706-713.  
19666475 L.A.Solt, L.A.Madge, and M.J.May (2009).
NEMO-binding domains of both IKKalpha and IKKbeta regulate IkappaB kinase complex assembly and classical NF-kappaB activation.
  J Biol Chem, 284, 27596-27608.  
19917246 M.Stilmann, M.Hinz, S.C.Arslan, A.Zimmer, V.Schreiber, and C.Scheidereit (2009).
A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation.
  Mol Cell, 36, 365-378.  
19303852 S.Rahighi, F.Ikeda, M.Kawasaki, M.Akutsu, N.Suzuki, R.Kato, T.Kensche, T.Uejima, S.Bloor, D.Komander, F.Randow, S.Wakatsuki, and I.Dikic (2009).
Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.
  Cell, 136, 1098-1109.
PDB codes: 2zvn 2zvo 3f89
  20066103 T.Huxford, and G.Ghosh (2009).
A structural guide to proteins of the NF-kappaB signaling module.
  Cold Spring Harbor Perspect Biol, 1, a000075.  
18668204 J.S.Orange, and M.J.May (2008).
Cell penetrating peptide inhibitors of nuclear factor-kappa B.
  Cell Mol Life Sci, 65, 3564-3591.  
18626576 L.A.Solt, and M.J.May (2008).
The IkappaB kinase complex: master regulator of NF-kappaB signaling.
  Immunol Res, 42, 3.  
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 codes are shown on the right.