PDBsum entry 2h2d

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Hydrolase PDB id
Protein chains
234 a.a. *
13 a.a. *
Waters ×179
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: The structural basis for sirtuin substrate affinity
Structure: NAD-dependent deacetylase. Chain: a. Fragment: sir2tm. Synonym: regulatory protein sir2 homolog. Engineered: yes. Cellular tumor antigen p53 peptide. Chain: b. Synonym: tumor suppressor p53, phosphoprotein p53, antigen engineered: yes
Source: Thermotoga maritima. Organism_taxid: 2336. Gene: npda. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the sequence of the peptide is naturally fou homo sapiens (human).
Biol. unit: Dimer (from PQS)
1.70Å     R-factor:   0.221     R-free:   0.237
Authors: M.S.Cosgrove,C.Wolberger
Key ref: M.S.Cosgrove et al. (2006). The structural basis of sirtuin substrate affinity. Biochemistry, 45, 7511-7521. PubMed id: 16768447 DOI: 10.1021/bi0526332
18-May-06     Release date:   19-Sep-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9WYW0  (NPD_THEMA) -  NAD-dependent protein deacetylase
246 a.a.
234 a.a.
Protein chain
Pfam   ArchSchema ?
P04637  (P53_HUMAN) -  Cellular tumor antigen p53
393 a.a.
13 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     protein deacetylation   1 term 
  Biochemical function     protein-malonyllysine demalonylase activity     8 terms  


DOI no: 10.1021/bi0526332 Biochemistry 45:7511-7521 (2006)
PubMed id: 16768447  
The structural basis of sirtuin substrate affinity.
M.S.Cosgrove, K.Bever, J.L.Avalos, S.Muhammad, X.Zhang, C.Wolberger.
Sirtuins comprise a family of enzymes that catalyze the deacetylation of acetyllysine side chains in a reaction that consumes NAD+. Although several crystal structures of sirtuins bound to non-native acetyl peptides have been determined, relatively little about how sirtuins discriminate among different substrates is understood. We have carried out a systematic structural and thermodynamic analysis of several peptides bound to a single sirtuin, the Sir2 homologue from Thermatoga maritima (Sir2Tm). We report structures of five different forms of Sir2Tm: two forms bound to the p53 C-terminal tail in the acetylated and unacetylated states, two forms bound to putative acetyl peptide substrates derived from the structured domains of histones H3 and H4, and one form bound to polypropylene glycol (PPG), which resembles the apoenzyme. The structures reveal previously unobserved complementary side chain interactions between Sir2Tm and the first residue N-terminal to the acetyllysine (position -1) and the second residue C-terminal to the acetyllysine (position +2). Isothermal titration calorimetry was used to compare binding constants between wild-type and mutant forms of Sir2Tm and between additional acetyl peptide substrates with substitutions at positions -1 and +2. The results are consistent with a model in which peptide positions -1 and +2 play a significant role in sirtuin substrate binding. This model provides a framework for identifying sirtuin substrates.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21071205 G.Schreiber, and A.E.Keating (2011).
Protein binding specificity versus promiscuity.
  Curr Opin Struct Biol, 21, 50-61.  
21080423 P.Bheda, J.T.Wang, J.C.Escalante-Semerena, and C.Wolberger (2011).
Structure of Sir2Tm bound to a propionylated peptide.
  Protein Sci, 20, 131-139.
PDB code: 3pdh
20877900 A.K.Verma, and R.Pratap (2010).
The biological potential of flavones.
  Nat Prod Rep, 27, 1571-1593.  
20601951 H.Wurtele, S.Tsao, G.Lépine, A.Mullick, J.Tremblay, P.Drogaris, E.H.Lee, P.Thibault, A.Verreault, and M.Raymond (2010).
Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy.
  Nat Med, 16, 774-780.  
19706170 K.S.Makarova, Y.I.Wolf, J.van der Oost, and E.V.Koonin (2009).
Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements.
  Biol Direct, 4, 29.  
19535340 L.Jin, W.Wei, Y.Jiang, H.Peng, J.Cai, C.Mao, H.Dai, W.Choy, J.E.Bemis, M.R.Jirousek, J.C.Milne, C.H.Westphal, and R.B.Perni (2009).
Crystal structures of human SIRT3 displaying substrate-induced conformational changes.
  J Biol Chem, 284, 24394-24405.
PDB codes: 3glr 3gls 3glt 3glu
19801667 W.F.Hawse, and C.Wolberger (2009).
Structure-based mechanism of ADP-ribosylation by sirtuins.
  J Biol Chem, 284, 33654-33661.  
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
17308975 A.L.Holme, and S.Pervaiz (2007).
Resveratrol in cell fate decisions.
  J Bioenerg Biomembr, 39, 59-63.  
17355872 A.Schuetz, J.Min, T.Antoshenko, C.L.Wang, A.Allali-Hassani, A.Dong, P.Loppnau, M.Vedadi, A.Bochkarev, R.Sternglanz, and A.N.Plotnikov (2007).
Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin.
  Structure, 15, 377-389.
PDB code: 2nyr
17705705 M.S.Cosgrove (2007).
Histone proteomics and the epigenetic regulation of nucleosome mobility.
  Expert Rev Proteomics, 4, 465-478.  
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