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PDBsum entry 2vje
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protein ligands metals Protein-protein interface(s) links
Ligase PDB id
2vje

 

 

 

 

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Contents
Protein chains
60 a.a. *
61 a.a. *
Ligands
FLC
SO4
Metals
_ZN ×8
Waters ×110
* Residue conservation analysis
PDB id:
2vje
Name: Ligase
Title: Crystal structure of the mdm2-mdmx ring domain heterodimer
Structure: E3 ubiquitin-protein ligase mdm2. Chain: a, c. Fragment: residues 383-446. Synonym: p53-binding protein mdm2, oncoprotein mdm2, double minute 2 protein, hdm2, mdm2. Engineered: yes. Mdm4 protein. Chain: b, d. Fragment: residues 428-490.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.20Å     R-factor:   0.198     R-free:   0.223
Authors: P.D.Mace,K.Linke,C.A.Smith,C.L.Day
Key ref: K.Linke et al. (2008). Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ, 15, 841-848. PubMed id: 18219319
Date:
10-Dec-07     Release date:   13-May-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q00987  (MDM2_HUMAN) -  E3 ubiquitin-protein ligase Mdm2 from Homo sapiens
Seq:
Struc: 		491 a.a.
60 a.a.
Protein chains
Pfam   ArchSchema ?
O15151  (MDM4_HUMAN) -  Protein Mdm4 from Homo sapiens
Seq:
Struc: 		490 a.a.
61 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.2.3.2.27  - RING-type E3 ubiquitin transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6- ubiquitinyl-[acceptor protein]-L-lysine

 

 
Cell Death Differ 15:841-848 (2008)
PubMed id: 18219319  
 
 
Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans.
K.Linke, P.D.Mace, C.A.Smith, D.L.Vaux, J.Silke, C.L.Day.
 
  ABSTRACT  
 
MDM2, a ubiquitin E3-ligase of the RING family, has a key role in regulating p53 abundance. During normal non-stress conditions p53 is targeted for degradation by MDM2. MDM2 can also target itself and MDMX for degradation. MDMX is closely related to MDM2 but the RING domain of MDMX does not possess intrinsic E3-ligase activity. Instead, MDMX regulates p53 abundance by modulating the levels and activity of MDM2. Dimerization, mediated by the conserved C-terminal RING domains of both MDM2 and MDMX, is critical to this activity. Here we report the crystal structure of the MDM2/MDMX RING domain heterodimer and map residues required for functional interaction with the E2 (UbcH5b). In both MDM2 and MDMX residues C-terminal to the RING domain have a key role in dimer formation. In addition we show that these residues are part of an extended surface that is essential for ubiquitylation in trans. This study provides a molecular basis for understanding how heterodimer formation leads to stabilization of MDM2, yet degradation of p53, and suggests novel targets for therapeutic intervention.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22902369 H.Dou, L.Buetow, G.J.Sibbet, K.Cameron, and D.T.Huang (2012).
BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer.
  Nat Struct Mol Biol, 19, 876-883.
PDB code: 4auq
21860393 A.M.Weissman, N.Shabek, and A.Ciechanover (2011).
The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation.
  Nat Rev Mol Cell Biol, 12, 605-620.  
21857666 A.Plechanovová, E.G.Jaffray, S.A.McMahon, K.A.Johnson, I.Navrátilová, J.H.Naismith, and R.T.Hay (2011).
Mechanism of ubiquitylation by dimeric RING ligase RNF4.
  Nat Struct Mol Biol, 18, 1052-1059.
PDB code: 2xeu
20975744 C.F.Cheok, C.S.Verma, J.Baselga, and D.P.Lane (2011).
Translating p53 into the clinic.
  Nat Rev Clin Oncol, 8, 25-37.  
21541195 K.Lenos, and A.G.Jochemsen (2011).
Functions of MDMX in the Modulation of the p53-Response.
  J Biomed Biotechnol, 2011, 876173.  
21863050 S.Lipkowitz, and A.M.Weissman (2011).
RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis.
  Nat Rev Cancer, 11, 629-643.  
  20516128 A.C.Joerger, and A.R.Fersht (2010).
The tumor suppressor p53: from structures to drug discovery.
  Cold Spring Harb Perspect Biol, 2, a000919.  
19557013 A.G.Eldridge, and T.O'Brien (2010).
Therapeutic strategies within the ubiquitin proteasome system.
  Cell Death Differ, 17, 4.  
20681948 C.W.Liew, H.Sun, T.Hunter, and C.L.Day (2010).
RING domain dimerization is essential for RNF4 function.
  Biochem J, 431, 23-29.
PDB code: 3ng2
19498444 J.C.Marine, and G.Lozano (2010).
Mdm2-mediated ubiquitylation: p53 and beyond.
  Cell Death Differ, 17, 93.  
20172729 M.Wade, Y.V.Wang, and G.M.Wahl (2010).
The p53 orchestra: Mdm2 and Mdmx set the tone.
  Trends Cell Biol, 20, 299-309.  
19838211 N.Allende-Vega, A.Sparks, D.P.Lane, and M.K.Saville (2010).
MdmX is a substrate for the deubiquitinating enzyme USP2a.
  Oncogene, 29, 432-441.  
19373243 P.D.Mace, S.Shirley, and C.L.Day (2010).
Assembling the building blocks: structure and function of inhibitor of apoptosis proteins.
  Cell Death Differ, 17, 46-53.  
  20081365 Q.Cheng, and J.Chen (2010).
Mechanism of p53 stabilization by ATM after DNA damage.
  Cell Cycle, 9, 472-478.  
20697359 S.Giglio, F.Mancini, M.Pellegrino, G.Di Conza, E.Puxeddu, A.Sacchi, A.Pontecorvi, and F.Moretti (2010).
Regulation of MDM4 (MDMX) function by p76(MDM2): a new facet in the control of p53 activity.
  Oncogene, 29, 5935-5945.  
19188367 B.Wawrzynow, S.Pettersson, A.Zylicz, J.Bramham, E.Worrall, T.R.Hupp, and K.L.Ball (2009).
A function for the RING finger domain in the allosteric control of MDM2 conformation and activity.
  J Biol Chem, 284, 11517-11530.  
19935675 C.J.Brown, S.Lain, C.S.Verma, A.R.Fersht, and D.P.Lane (2009).
Awakening guardian angels: drugging the p53 pathway.
  Nat Rev Cancer, 9, 862-873.  
19712108 D.E.Christensen, and R.E.Klevit (2009).
Dynamic interactions of proteins in complex networks: identifying the complete set of interacting E2s for functional investigation of E3-dependent protein ubiquitination.
  FEBS J, 276, 5381-5389.  
19568783 E.G.Worrall, B.Wawrzynow, L.Worrall, M.Walkinshaw, K.L.Ball, and T.R.Hupp (2009).
Regulation of the E3 ubiquitin ligase activity of MDM2 by an N-terminal pseudo-substrate motif.
  J Chem Biol, 2, 113-129.  
19721810 F.Mancini, G.D.Conza, and F.Moretti (2009).
MDM4 (MDMX) and its Transcript Variants.
  Curr Genomics, 10, 42-50.  
19147532 M.Wade, and G.M.Wahl (2009).
Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
  Mol Cancer Res, 7, 1.  
19573810 Y.V.Wang, M.Leblanc, M.Wade, A.G.Jochemsen, and G.M.Wahl (2009).
Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases.
  Cancer Cell, 16, 33-43.  
19738896 J.A.Lehman, J.A.Eitel, C.N.Batuello, and L.D.Mayo (2008).
Therapeutic considerations for Mdm2: not just a one trick pony.
  Expert Opin Drug Discov, 3, 1309-1321.  
18784070 P.D.Mace, K.Linke, R.Feltham, F.R.Schumacher, C.A.Smith, D.L.Vaux, J.Silke, and C.L.Day (2008).
Structures of the cIAP2 RING Domain Reveal Conformational Changes Associated with Ubiquitin-conjugating Enzyme (E2) Recruitment.
  J Biol Chem, 283, 31633-31640.
PDB codes: 3eb5 3eb6
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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