PDBsum entry 1yy6

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Hydrolase PDB id
Protein chain
137 a.a. *
_NA ×21
Waters ×186
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: The crystal strucure of the n-terminal domain of hausp/usp7 complexed with an ebna1 peptide
Structure: Ubiquitin carboxyl-terminal hydrolase 7. Chain: a. Synonym: ubiquitin thiolesterase 7, ubiquitin-specific processing protease 7, deubiquitinating enzyme 7, herpesvirus associated ubiquitin-specific protease, usp7, hausp. Engineered: yes. Epstein-barr nuclear antigen-1. Chain: b.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: usp7, hausp. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Synthetic: yes. Other_details: the sequence of the peptide can be found naturally in epstein-barr virus
Biol. unit: Dimer (from PQS)
1.70Å     R-factor:   0.198     R-free:   0.230
Authors: V.Saridakis,Y.Sheng,F.Sarkari,M.Holowaty,K.Shire,T.Nguyen, R.Zhang,J.Liao,W.Lee,A.M.Edwards,C.H.Arrowsmith,L.Frappier
Key ref:
V.Saridakis et al. (2005). Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell, 18, 25-36. PubMed id: 15808506 DOI: 10.1016/j.molcel.2005.02.029
23-Feb-05     Release date:   05-Apr-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q93009  (UBP7_HUMAN) -  Ubiquitin carboxyl-terminal hydrolase 7
1102 a.a.
137 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Ubiquitinyl hydrolase 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).


DOI no: 10.1016/j.molcel.2005.02.029 Mol Cell 18:25-36 (2005)
PubMed id: 15808506  
Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.
V.Saridakis, Y.Sheng, F.Sarkari, M.N.Holowaty, K.Shire, T.Nguyen, R.G.Zhang, J.Liao, W.Lee, A.M.Edwards, C.H.Arrowsmith, L.Frappier.
USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.
  Selected figure(s)  
Figure 1.
Figure 1. Crystal Structure of the USP7 NTD with EBNA1 Peptide
Figure 3.
Figure 3. The Path and Contacts of the EBNA1 Peptide Bound to USP7
  The above figures are reprinted by permission from Cell Press: Mol Cell (2005, 18, 25-36) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22056774 H.R.Lee, W.C.Choi, S.Lee, J.Hwang, E.Hwang, K.Guchhait, J.Haas, Z.Toth, Y.H.Jeon, T.K.Oh, M.H.Kim, and J.U.Jung (2011).
Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.
  Nat Struct Mol Biol, 18, 1336-1344.
PDB code: 2xxn
21052088 J.Iqbal, D.D.Weisenburger, A.Chowdhury, M.Y.Tsai, G.Srivastava, T.C.Greiner, C.Kucuk, K.Deffenbacher, J.Vose, L.Smith, W.Y.Au, S.Nakamura, M.Seto, J.Delabie, F.Berger, F.Loong, Y.H.Ko, I.Sng, X.Liu, T.P.Loughran, J.Armitage, and W.C.Chan (2011).
Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro.
  Leukemia, 25, 348-358.  
21411309 L.Frappier, and C.P.Verrijzer (2011).
Gene expression control by protein deubiquitinases.
  Curr Opin Genet Dev, 21, 207-213.  
21170034 M.T.Epping, L.A.Meijer, O.Krijgsman, J.L.Bos, P.P.Pandolfi, and R.Bernards (2011).
TSPYL5 suppresses p53 levels and function by physical interaction with USP7.
  Nat Cell Biol, 13, 102-108.  
21146412 N.E.Davey, G.Travé, and T.J.Gibson (2011).
How viruses hijack cell regulation.
  Trends Biochem Sci, 36, 159-169.  
20730552 S.Ramakrishna, B.Suresh, and K.H.Baek (2011).
The role of deubiquitinating enzymes in apoptosis.
  Cell Mol Life Sci, 68, 15-26.  
21258371 Z.Huang, Q.Wu, O.A.Guryanova, L.Cheng, W.Shou, J.N.Rich, and S.Bao (2011).
Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells.
  Nat Cell Biol, 13, 142-152.  
20042495 A.Watanabe, S.Maruo, T.Ito, M.Ito, K.R.Katsumura, and K.Takada (2010).
Epstein-Barr virus-encoded Bcl-2 homologue functions as a survival factor in Wp-restricted Burkitt lymphoma cell line P3HR-1.
  J Virol, 84, 2893-2901.  
20885946 F.Sarkari, Y.Sheng, and L.Frappier (2010).
USP7/HAUSP promotes the sequence-specific DNA binding activity of p53.
  PLoS One, 5, e13040.  
20219917 I.Tempera, Z.Deng, C.Atanasiu, C.J.Chen, M.D'Erme, and P.M.Lieberman (2010).
Regulation of Epstein-Barr virus OriP replication by poly(ADP-ribose) polymerase 1.
  J Virol, 84, 4988-4997.  
20210752 M.L.Bellows, and C.A.Floudas (2010).
Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.
  Curr Drug Targets, 11, 264-278.  
20190741 S.Gastaldello, S.Hildebrand, O.Faridani, S.Callegari, M.Palmkvist, C.Di Guglielmo, and M.G.Masucci (2010).
A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases.
  Nat Cell Biol, 12, 351-361.  
19793909 S.Iwata, K.Wada, S.Tobita, K.Gotoh, Y.Ito, A.Demachi-Okamura, N.Shimizu, Y.Nishiyama, and H.Kimura (2010).
Quantitative analysis of Epstein-Barr virus (EBV)-related gene expression in patients with chronic active EBV infection.
  J Gen Virol, 91, 42-50.  
20133771 X.Sun, E.A.Barlow, S.Ma, S.R.Hagemeier, S.J.Duellman, R.R.Burgess, J.Tellam, R.Khanna, and S.C.Kenney (2010).
Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism.
  Proc Natl Acad Sci U S A, 107, 3146-3151.  
19244339 A.Saha, M.Murakami, P.Kumar, B.Bajaj, K.Sims, and E.S.Robertson (2009).
Epstein-Barr virus nuclear antigen 3C augments Mdm2-mediated p53 ubiquitination and degradation by deubiquitinating Mdm2.
  J Virol, 83, 4652-4669.  
19619655 B.Gruhne, S.A.Kamranvar, M.G.Masucci, and R.Sompallae (2009).
EBV and genomic instability--a new look at the role of the virus in the pathogenesis of Burkitt's lymphoma.
  Semin Cancer Biol, 19, 394-400.  
19628040 D.Vereide, and B.Sugden (2009).
Proof for EBV's sustaining role in Burkitt's lymphomas.
  Semin Cancer Biol, 19, 389-393.  
19489724 F.E.Reyes-Turcu, K.H.Ventii, and K.D.Wilkinson (2009).
Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.
  Annu Rev Biochem, 78, 363-397.  
19834552 F.Sarkari, T.Sanchez-Alcaraz, S.Wang, M.N.Holowaty, Y.Sheng, and L.Frappier (2009).
EBNA1-mediated recruitment of a histone H2B deubiquitylating complex to the Epstein-Barr virus latent origin of DNA replication.
  PLoS Pathog, 5, e1000624.  
19165855 G.W.Bornkamm (2009).
Epstein-Barr virus and the pathogenesis of Burkitt's lymphoma: more questions than answers.
  Int J Cancer, 124, 1745-1755.  
19619654 G.W.Bornkamm (2009).
Epstein-Barr virus and its role in the pathogenesis of Burkitt's lymphoma: an unresolved issue.
  Semin Cancer Biol, 19, 351-365.  
19635566 M.J.Allday (2009).
How does Epstein-Barr virus (EBV) complement the activation of Myc in the pathogenesis of Burkitt's lymphoma?
  Semin Cancer Biol, 19, 366-376.  
18952891 S.Daubeuf, D.Singh, Y.Tan, H.Liu, H.J.Federoff, W.J.Bowers, and K.Tolba (2009).
HSV ICP0 recruits USP7 to modulate TLR-mediated innate response.
  Blood, 113, 3264-3275.  
18410486 J.A.Nathan, S.Sengupta, S.A.Wood, A.Admon, G.Markson, C.Sanderson, and P.J.Lehner (2008).
The ubiquitin E3 ligase MARCH7 is differentially regulated by the deubiquitylating enzymes USP7 and USP9X.
  Traffic, 9, 1130-1145.  
19013244 J.M.Middeldorp, and D.M.Pegtel (2008).
Multiple roles of LMP1 in Epstein-Barr virus induced immune escape.
  Semin Cancer Biol, 18, 388-396.  
18442057 M.K.Chen, J.C.Lai, C.C.Chang, J.H.Chang, Y.J.Chang, and H.C.Chen (2008).
Prognostic impact of bcl-2 expression on advanced nasopharyngeal carcinoma.
  Head Neck, 30, 1052-1057.  
18256159 M.S.Kang, V.Soni, R.Bronson, and E.Kieff (2008).
Epstein-Barr virus nuclear antigen 1 does not cause lymphoma in C57BL/6J mice.
  J Virol, 82, 4180-4183.  
18833293 N.Sivachandran, F.Sarkari, and L.Frappier (2008).
Epstein-Barr nuclear antigen 1 contributes to nasopharyngeal carcinoma through disruption of PML nuclear bodies.
  PLoS Pathog, 4, e1000170.  
18931080 P.Tsimbouri, Y.Al-Sheikh, M.E.Drotar, W.Cushley, and J.B.Wilson (2008).
Epstein-Barr virus nuclear antigen-1 renders lymphocytes responsive to IL-2 but not IL-15 for survival.
  J Gen Virol, 89, 2821-2832.  
19007433 S.Singhal, M.C.Taylor, and R.T.Baker (2008).
Deubiquitylating enzymes and disease.
  BMC Biochem, 9, S3.  
17651432 A.Fernández-Montalván, T.Bouwmeester, G.Joberty, R.Mader, M.Mahnke, B.Pierrat, J.M.Schlaeppi, S.Worpenberg, and B.Gerhartz (2007).
Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.
  FEBS J, 274, 4256-4270.  
17229074 A.L.Snow, and O.M.Martinez (2007).
Epstein-Barr virus: evasive maneuvers in the development of PTLD.
  Am J Transplant, 7, 271-277.  
17381419 B.Nicholson, J.G.Marblestone, T.R.Butt, and M.R.Mattern (2007).
Deubiquitinating enzymes as novel anticancer targets.
  Future Oncol, 3, 191-199.  
17554050 K.L.Maxwell, and L.Frappier (2007).
Viral proteomics.
  Microbiol Mol Biol Rev, 71, 398-411.  
17632125 K.Li, B.Ossareh-Nazari, X.Liu, C.Dargemont, and R.Marmorstein (2007).
Molecular basis for bre5 cofactor recognition by the ubp3 deubiquitylating enzyme.
  J Mol Biol, 372, 194-204.
PDB code: 2qiy
17640300 K.Noguchi, H.Fukazawa, Y.Murakami, N.Takahashi, S.Yamagoe, and Y.Uehara (2007).
Gamma-herpesviruses and cellular signaling in AIDS-associated malignancies.
  Cancer Sci, 98, 1288-1296.  
18047738 P.Guédat, and F.Colland (2007).
Patented small molecule inhibitors in the ubiquitin proteasome system.
  BMC Biochem, 8, S14.  
17350094 S.E.Lindner, and B.Sugden (2007).
The plasmid replicon of Epstein-Barr virus: mechanistic insights into efficient, licensed, extrachromosomal replication in human cells.
  Plasmid, 58, 1.  
17486072 V.H.Wood, J.D.O'Neil, W.Wei, S.E.Stewart, C.W.Dawson, and L.S.Young (2007).
Epstein-Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFbeta signaling pathways.
  Oncogene, 26, 4135-4147.  
17446669 D.Iwakiri, M.Samanta, and K.Takada (2006).
[Mechanisms of EBV-mediated oncogenesis]
  Uirusu, 56, 201-208.  
16987979 J.O'Nions, A.Turner, R.Craig, and M.J.Allday (2006).
Epstein-Barr virus selectively deregulates DNA damage responses in normal B cells but has no detectable effect on regulation of the tumor suppressor p53.
  J Virol, 80, 12408-12413.  
16699006 K.Shire, P.Kapoor, K.Jiang, M.N.Hing, N.Sivachandran, T.Nguyen, and L.Frappier (2006).
Regulation of the EBNA1 Epstein-Barr virus protein by serine phosphorylation and arginine methylation.
  J Virol, 80, 5261-5272.  
16402859 M.Hu, L.Gu, M.Li, P.D.Jeffrey, W.Gu, and Y.Shi (2006).
Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.
  PLoS Biol, 4, e27.
PDB codes: 2f1w 2f1x 2f1y 2f1z
16298993 Jong, E.Ab, T.Diercks, V.Truffault, M.Daniëls, R.Kaptein, and G.E.Folkers (2006).
Solution structure of the human ubiquitin-specific protease 15 DUSP domain.
  J Biol Chem, 281, 5026-5031.
PDB code: 1w6v
16913834 T.Sulea, H.A.Lindner, and R.Ménard (2006).
Structural aspects of recently discovered viral deubiquitinating activities.
  Biol Chem, 387, 853-862.  
16957053 Y.J.Machida, Y.Chen, Y.Machida, A.Malhotra, S.Sarkar, and A.Dutta (2006).
Targeted comparative RNA interference analysis reveals differential requirement of genes essential for cell proliferation.
  Mol Biol Cell, 17, 4837-4845.  
16474402 Y.Sheng, V.Saridakis, F.Sarkari, S.Duan, T.Wu, C.H.Arrowsmith, and L.Frappier (2006).
Molecular recognition of p53 and MDM2 by USP7/HAUSP.
  Nat Struct Mol Biol, 13, 285-291.
PDB codes: 2foj 2foo 2fop
16557009 S.Imai, M.Kuroda, R.Yamashita, and Y.Ishiura (2005).
[Therapeutic inhibition of Epstein-Barr virus-associated tumor cell growth by dominant-negative EBNA1]
  Uirusu, 55, 239-249.  
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.