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PDBsum entry 1szd

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protein ligands metals links
Gene regulation PDB id
1szd
Jmol
Contents
Protein chain
291 a.a. *
Ligands
LYS-GLY-GLY-ALA-
ALY-ARG-HIS-ARG
APR
GOL ×3
Metals
_CL
_ZN
Waters ×340
* Residue conservation analysis
PDB id:
1szd
Name: Gene regulation
Title: Structural basis for nicotinamide cleavage and adp-ribose tr NAD+-dependent sir2 histone/protein deacetylases
Structure: NAD-dependent deacetylase hst2. Chain: a. Fragment: catalytic core domain. Synonym: homologous to sir2 protein 2. Engineered: yes. Histone h4 peptide. Chain: b. Engineered: yes
Source: Saccharomyces cerevisiae. Baker's yeast. Organism_taxid: 4932. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: the peptide was chemically synthesized. The of the peptide naturally occurs in saccharomyces cerevisiae yeast).
Biol. unit: Tetramer (from PQS)
Resolution:
1.50Å     R-factor:   0.214     R-free:   0.230
Authors: K.Zhao,R.Harshaw,X.Chai,R.Marmorstein
Key ref:
K.Zhao et al. (2004). Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. Proc Natl Acad Sci U S A, 101, 8563-8568. PubMed id: 15150415 DOI: 10.1073/pnas.0401057101
Date:
05-Apr-04     Release date:   15-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P53686  (HST2_YEAST) -  NAD-dependent protein deacetylase HST2
Seq:
Struc:
357 a.a.
291 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein deacetylation   1 term 
  Biochemical function     hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides     4 terms  

 

 
DOI no: 10.1073/pnas.0401057101 Proc Natl Acad Sci U S A 101:8563-8568 (2004)
PubMed id: 15150415  
 
 
Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases.
K.Zhao, R.Harshaw, X.Chai, R.Marmorstein.
 
  ABSTRACT  
 
Sir2 enzymes are broadly conserved from bacteria to humans and have been implicated to play roles in gene silencing, DNA repair, genome stability, longevity, metabolism, and cell physiology. These enzymes bind NAD(+) and acetyllysine within protein targets and generate lysine, 2'-O-acetyl-ADP-ribose, and nicotinamide products. To provide structural insights into the chemistry catalyzed by Sir2 proteins we report the high-resolution ternary structure of yeast Hst2 (homologue of Sir two 2) with an acetyllysine histone H4 peptide and a nonhydrolyzable NAD(+) analogue, carba-NAD(+), as well as an analogous ternary complex with a reaction intermediate analog formed immediately after nicotinamide hydrolysis, ADP-ribose. The ternary complex with carba-NAD(+) reveals that the nicotinamide group makes stabilizing interactions within a binding pocket harboring conserved Sir2 residues. Moreover, an asparagine residue, N116, strictly conserved within Sir2 proteins and shown to be essential for nicotinamide exchange, is in position to stabilize the oxocarbenium intermediate that has been proposed to proceed the hydrolysis of nicotinamide. A comparison of this structure with the ADP-ribose ternary complex and a previously reported ternary complex with the 2'-O-acetyl-ADP-ribose reaction product reveals that the ribose ring of the cofactor and the highly conserved beta1-alpha2 loop of the protein undergo significant structural rearrangements to facilitate the ordered NAD(+) reactions of nicotinamide cleavage and ADP-ribose transfer to acetate. Together, these studies provide insights into the chemistry of NAD(+) cleavage and acetylation by Sir2 proteins and have implications for the design of Sir2-specific regulatory molecules.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. The yHst2 nicotinamide-binding site. (a) van der Waals surface of yHst2/carba-NAD^+/H4 highlighting invariant residues (blue) as well as the subset of these residues that contact nicotinamide (red). I117, which contacts nicotinamide, is also highlighted in red, although this residue has not been subjected to mutagenesis. The surface for the 1- 2 NAD^+-binding loop is deleted from this image for clarity. (b) Stereoview of yHst2-nicotinamide interactions, with hydrogen bonds depicted as dotted lines. Protein residues that mediate van der Waals interactions with the nicotinamide are also highlighted. yHst2 and carba-NAD^+ color-coding is as in Fig. 2a.
Figure 4.
Fig. 4. Proposed catalytic mechanism for yHst2.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21243715 K.E.Dittenhafer-Reed, J.L.Feldman, and J.M.Denu (2011).
Catalysis and mechanistic insights into sirtuin activation.
  Chembiochem, 12, 281-289.  
  20221297 J.S.Sonneborn (2010).
Mimetics of hormetic agents: stress-resistance triggers.
  Dose Response, 8, 97.  
19716529 A.Saini, S.Faulkner, N.Al-Shanti, and C.Stewart (2009).
Powerful signals for weak muscles.
  Ageing Res Rev, 8, 251-267.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
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
19721249 T.Suzuki (2009).
Explorative study on isoform-selective histone deacetylase inhibitors.
  Chem Pharm Bull (Tokyo), 57, 897-906.  
19523169 Y.Hayashi, T.Senda, N.Sano, and M.Horikoshi (2009).
Theoretical framework for the histone modification network: modifications in the unstructured histone tails form a robust scale-free network.
  Genes Cells, 14, 789-806.  
18940661 B.C.Smith, W.C.Hallows, and J.M.Denu (2008).
Mechanisms and molecular probes of sirtuins.
  Chem Biol, 15, 1002-1013.  
19806227 I.Autiero, S.Costantini, and G.Colonna (2008).
Human sirt-1: molecular modeling and structure-function relationships of an unordered protein.
  PLoS One, 4, e7350.  
18586844 J.A.Kovacs, M.Yeager, and R.Abagyan (2008).
Damped-dynamics flexible fitting.
  Biophys J, 95, 3192-3207.  
19049465 P.Hu, S.Wang, and Y.Zhang (2008).
Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by ab initio QM/MM molecular dynamics simulations.
  J Am Chem Soc, 130, 16721-16728.  
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
17289592 B.D.Sanders, K.Zhao, J.T.Slama, and R.Marmorstein (2007).
Structural basis for nicotinamide inhibition and base exchange in Sir2 enzymes.
  Mol Cell, 25, 463-472.
PDB codes: 2od2 2od7 2od9 2qqf 2qqg
18019526 H.Lin (2007).
Nicotinamide adenine dinucleotide: beyond a redox coenzyme.
  Org Biomol Chem, 5, 2541-2554.  
17156081 H.Yang, J.A.Baur, A.Chen, C.Miller, J.K.Adams, A.Kisielewski, K.T.Howitz, R.E.Zipkin, and D.A.Sinclair (2007).
Design and synthesis of compounds that extend yeast replicative lifespan.
  Aging Cell, 6, 35-43.  
17242192 J.Mead, R.McCord, L.Youngster, M.Sharma, M.R.Gartenberg, and A.K.Vershon (2007).
Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases.
  Mol Cell Biol, 27, 2466-2475.  
17694092 S.C.Hodawadekar, and R.Marmorstein (2007).
Chemistry of acetyl transfer by histone modifying enzymes: structure, mechanism and implications for effector design.
  Oncogene, 26, 5528-5540.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
16756498 A.A.Sauve, C.Wolberger, V.L.Schramm, and J.D.Boeke (2006).
The biochemistry of sirtuins.
  Annu Rev Biochem, 75, 435-465.  
16388603 B.C.Smith, and J.M.Denu (2006).
Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine.
  Biochemistry, 45, 272-282.  
16905094 B.C.Smith, and J.M.Denu (2006).
Sirtuins caught in the act.
  Structure, 14, 1207-1208.  
17035629 B.Yang, and A.L.Kirchmaier (2006).
Bypassing the catalytic activity of SIR2 for SIR protein spreading in Saccharomyces cerevisiae.
  Mol Biol Cell, 17, 5287-5297.  
16905097 K.G.Hoff, J.L.Avalos, K.Sens, and C.Wolberger (2006).
Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide.
  Structure, 14, 1231-1240.
PDB codes: 2h4f 2h4h 2h4j 2h59
16959969 P.O.Hassa, S.S.Haenni, M.Elser, and M.O.Hottiger (2006).
Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going?
  Microbiol Mol Biol Rev, 70, 789-829.  
17103016 T.Huhtiniemi, C.Wittekindt, T.Laitinen, J.Leppänen, A.Salminen, A.Poso, and M.Lahtela-Kakkonen (2006).
Comparative and pharmacophore model for deacetylase SIRT1.
  J Comput Aided Mol Des, 20, 589-599.  
16986202 T.Suzuki, K.Imai, H.Nakagawa, and N.Miyata (2006).
2-Anilinobenzamides as SIRT inhibitors.
  ChemMedChem, 1, 1059-1062.  
16980972 Y.Tang, M.V.Poustovoitov, K.Zhao, M.Garfinkel, A.Canutescu, R.Dunbrack, P.D.Adams, and R.Marmorstein (2006).
Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly.
  Nat Struct Mol Biol, 13, 921-929.
PDB code: 2i32
15780941 J.L.Avalos, K.M.Bever, and C.Wolberger (2005).
Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme.
  Mol Cell, 17, 855-868.
PDB codes: 1yc2 1yc5
16039130 J.M.Denu (2005).
Vitamin B3 and sirtuin function.
  Trends Biochem Sci, 30, 479-483.  
16122969 J.M.Denu (2005).
The Sir 2 family of protein deacetylases.
  Curr Opin Chem Biol, 9, 431-440.  
15898057 M.Biel, V.Wascholowski, and A.Giannis (2005).
Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.
  Angew Chem Int Ed Engl, 44, 3186-3216.  
15681027 M.Porcu, and A.Chiarugi (2005).
The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension.
  Trends Pharmacol Sci, 26, 94.  
15611301 R.Sawaya, B.Schwer, and S.Shuman (2005).
Structure-function analysis of the yeast NAD+-dependent tRNA 2'-phosphotransferase Tpt1.
  RNA, 11, 107-113.  
16006743 S.Hisahara, S.Chiba, H.Matsumoto, and Y.Horio (2005).
Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2alpha).
  J Pharmacol Sci, 98, 200-204.  
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.