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PDBsum entry 2dyh
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Transcription PDB id
2dyh

 

 

 

 

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Contents
Protein chain
296 a.a. *
Ligands
TRP-ARG-GLN-ASP-
ILE-ASP
SO4 ×7
Waters ×307
* Residue conservation analysis
PDB id:
2dyh
Name: Transcription
Title: Crystal structure of the keap1 protein in complexed with the n- terminal region of the nrf2 transcription factor
Structure: Kelch-like ech-associated protein 1. Chain: a. Fragment: keap1-dc. Synonym: keap1, cytosolic inhibitor of nrf2. Engineered: yes. Nrf2/neh2 peptide from nuclear factor erythroid 2-related factor 2. Chain: b. Synonym: nf-e2-related factor 2, nfe2-related factor 2, nuclear
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: nrf2 peptide, synthetic peptide
Resolution:
1.90Å     R-factor:   0.174     R-free:   0.211
Authors: B.Padmanabhan,S.Yokoyama,Riken Structural Genomics/proteomics Initiative (Rsgi)
Key ref: K.I.Tong et al. (2007). Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol, 27, 7511-7521. PubMed id: 17785452
Date:
14-Sep-06     Release date:   04-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Z2X8  (KEAP1_MOUSE) -  Kelch-like ECH-associated protein 1 from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		624 a.a.
296 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
Mol Cell Biol 27:7511-7521 (2007)
PubMed id: 17785452  
 
 
Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response.
K.I.Tong, B.Padmanabhan, A.Kobayashi, C.Shang, Y.Hirotsu, S.Yokoyama, M.Yamamoto.
 
  ABSTRACT  
 
Nrf2 is the regulator of the oxidative/electrophilic stress response. Its turnover is maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge and latch. The E3 ligase adaptor Keap1 recognizes Nrf2 through its conserved ETGE and DLG motifs. In this study, we examined how the ETGE and DLG motifs bind to Keap1 in a very similar fashion but with different binding affinities by comparing the crystal complex of a Keap1-DC domain-DLG peptide with that of a Keap1-DC domain-ETGE peptide. We found that these two motifs interact with the same basic surface of either Keap1-DC domain of the Keap1 homodimer. The DLG motif works to correctly position the lysines within the Nrf2 Neh2 domain for efficient ubiquitination. Together with the results from calorimetric and functional studies, we conclude that different electrostatic potentials primarily define the ETGE and DLG motifs as a hinge and latch that senses the oxidative/electrophilic stress.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22266938 L.M.Boyden, M.Choi, K.A.Choate, C.J.Nelson-Williams, A.Farhi, H.R.Toka, I.R.Tikhonova, R.Bjornson, S.M.Mane, G.Colussi, M.Lebel, R.D.Gordon, B.A.Semmekrot, A.Poujol, M.J.Välimäki, M.E.De Ferrari, S.A.Sanjad, M.Gutkin, F.E.Karet, J.R.Tucci, J.R.Stockigt, K.M.Keppler-Noreuil, C.C.Porter, S.K.Anand, M.L.Whiteford, I.D.Davis, S.B.Dewar, A.Bettinelli, J.J.Fadrowski, C.W.Belsha, T.E.Hunley, R.D.Nelson, H.Trachtman, T.R.Cole, M.Pinsk, D.Bockenhauer, M.Shenoy, P.Vaidyanathan, J.W.Foreman, M.Rasoulpour, F.Thameem, H.Z.Al-Shahrouri, J.Radhakrishnan, A.G.Gharavi, B.Goilav, and R.P.Lifton (2012).
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
  Nature, 482, 98.  
21365312 L.Baird, and A.T.Dinkova-Kostova (2011).
The cytoprotective role of the Keap1-Nrf2 pathway.
  Arch Toxicol, 85, 241-272.  
20215646 G.P.Sykiotis, and D.Bohmann (2010).
Stress-activated cap'n'collar transcription factors in aging and human disease.
  Sci Signal, 3, re3.  
20446770 J.Shlomai (2010).
Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication.
  Antioxid Redox Signal, 13, 1429-1476.  
20173742 M.Komatsu, H.Kurokawa, S.Waguri, K.Taguchi, A.Kobayashi, Y.Ichimura, Y.S.Sou, I.Ueno, A.Sakamoto, K.I.Tong, M.Kim, Y.Nishito, S.Iemura, T.Natsume, T.Ueno, E.Kominami, H.Motohashi, K.Tanaka, and M.Yamamoto (2010).
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.
  Nat Cell Biol, 12, 213-223.
PDB code: 3ade
20837051 R.C.Siow, and G.E.Mann (2010).
Dietary isoflavones and vascular protection: activation of cellular antioxidant defenses by SERMs or hormesis?
  Mol Aspects Med, 31, 468-477.  
20486765 R.Hu, C.L.Saw, R.Yu, and A.N.Kong (2010).
Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory.
  Antioxid Redox Signal, 13, 1679-1698.  
20133743 T.Ogura, K.I.Tong, K.Mio, Y.Maruyama, H.Kurokawa, C.Sato, and M.Yamamoto (2010).
Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains.
  Proc Natl Acad Sci U S A, 107, 2842-2847.  
20446769 V.Calabrese, C.Cornelius, A.T.Dinkova-Kostova, E.J.Calabrese, and M.P.Mattson (2010).
Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders.
  Antioxid Redox Signal, 13, 1763-1811.  
20139631 Y.Nakamura, and N.Miyoshi (2010).
Electrophiles in foods: the current status of isothiocyanates and their chemical biology.
  Biosci Biotechnol Biochem, 74, 242-255.  
19489739 A.L.Eggler, E.Small, M.Hannink, and A.D.Mesecar (2009).
Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1.
  Biochem J, 422, 171-180.  
19573595 E.Kansanen, A.M.Kivelä, and A.L.Levonen (2009).
Regulation of Nrf2-dependent gene expression by 15-deoxy-Delta12,14-prostaglandin J2.
  Free Radic Biol Med, 47, 1310-1317.  
19573594 F.Zhao, T.Wu, A.Lau, T.Jiang, Z.Huang, X.J.Wang, W.Chen, P.K.Wong, and D.D.Zhang (2009).
Nrf2 promotes neuronal cell differentiation.
  Free Radic Biol Med, 47, 867-879.  
19751820 G.S.Shim, S.Manandhar, D.H.Shin, T.H.Kim, and M.K.Kwak (2009).
Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway.
  Free Radic Biol Med, 47, 1619-1631.  
18717631 J.Clark, and D.K.Simon (2009).
Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease.
  Antioxid Redox Signal, 11, 509-528.  
19321346 J.D.Hayes, and M.McMahon (2009).
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer.
  Trends Biochem Sci, 34, 176-188.  
19179352 L.Gao, and G.E.Mann (2009).
Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling.
  Cardiovasc Res, 82, 9.  
19818708 M.Zhuang, M.F.Calabrese, J.Liu, M.B.Waddell, A.Nourse, M.Hammel, D.J.Miller, H.Walden, D.M.Duda, S.N.Seyedin, T.Hoggard, J.W.Harper, K.P.White, and B.A.Schulman (2009).
Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases.
  Mol Cell, 36, 39-50.
PDB codes: 3hqh 3hqi 3hql 3hqm 3hsv 3htm 3hu6 3hve 3ivq 3ivv
19785463 R.Holland, M.Navamal, M.Velayutham, J.L.Zweier, T.W.Kensler, and J.C.Fishbein (2009).
Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones.
  Chem Res Toxicol, 22, 1427-1434.  
19560419 W.Chen, Z.Sun, X.J.Wang, T.Jiang, Z.Huang, D.Fang, and D.D.Zhang (2009).
Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response.
  Mol Cell, 34, 663-673.  
18618599 W.Li, and A.N.Kong (2009).
Molecular mechanisms of Nrf2-mediated antioxidant response.
  Mol Carcinog, 48, 91.  
19273602 Z.Sun, Y.E.Chin, and D.D.Zhang (2009).
Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response.
  Mol Cell Biol, 29, 2658-2672.  
19668370 Z.Sun, Z.Huang, and D.D.Zhang (2009).
Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response.
  PLoS One, 4, e6588.  
18421157 B.Padmanabhan, K.I.Tong, A.Kobayashi, M.Yamamoto, and S.Yokoyama (2008).
Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1.
  J Synchrotron Radiat, 15, 273-276.  
  18391415 B.Padmanabhan, Y.Nakamura, and S.Yokoyama (2008).
Structural analysis of the complex of Keap1 with a prothymosin alpha peptide.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 233-238.
PDB code: 2z32
19060448 T.Mamiya, F.Katsuoka, A.Hirayama, O.Nakajima, A.Kobayashi, J.M.Maher, H.Matsui, I.Hyodo, M.Yamamoto, and T.Hosoya (2008).
Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in basal and oxidative environments.
  Tohoku J Exp Med, 216, 331-339.  
18757741 T.Shibata, T.Ohta, K.I.Tong, A.Kokubu, R.Odogawa, K.Tsuta, H.Asamura, M.Yamamoto, and S.Hirohashi (2008).
Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.
  Proc Natl Acad Sci U S A, 105, 13568-13573.  
18268004 T.Yamamoto, T.Suzuki, A.Kobayashi, J.Wakabayashi, J.Maher, H.Motohashi, and M.Yamamoto (2008).
Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity.
  Mol Cell Biol, 28, 2758-2770.  
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.

 

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