PDBsum entry 2dew

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protein ligands metals links
Hydrolase PDB id
Protein chain
629 a.a. *
SO4 ×3
_CA ×5
Waters ×224
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of human peptidylarginine deiminase 4 in c with histone h3 n-terminal tail including arg8
Structure: Protein-arginine deiminase type iv. Chain: x. Synonym: peptidylarginine deiminase iv, hl-60 pad, peptidyl deiminase 4. Engineered: yes. Mutation: yes. 10-mer peptide from histone h3. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: padi4, padi5, pdi5. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: the peptide was chemically synthesized.
Biol. unit: Tetramer (from PDB file)
2.10Å     R-factor:   0.206     R-free:   0.241
Authors: K.Arita,T.Shimizu,H.Hashimoto,Y.Hidaka,M.Yamada,M.Sato
Key ref:
K.Arita et al. (2006). Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4. Proc Natl Acad Sci U S A, 103, 5291-5296. PubMed id: 16567635 DOI: 10.1073/pnas.0509639103
18-Feb-06     Release date:   11-Apr-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9UM07  (PADI4_HUMAN) -  Protein-arginine deiminase type-4
663 a.a.
629 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Protein-arginine deiminase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein L-arginine + H2O = protein L-citrulline + NH3
Protein L-arginine
Bound ligand (Het Group name = ARG)
matches with 68.75% similarity
+ H(2)O
= protein L-citrulline
+ NH(3)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   2 terms 
  Biological process     immune system process   12 terms 
  Biochemical function     protein binding     6 terms  


    Added reference    
DOI no: 10.1073/pnas.0509639103 Proc Natl Acad Sci U S A 103:5291-5296 (2006)
PubMed id: 16567635  
Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4.
K.Arita, T.Shimizu, H.Hashimoto, Y.Hidaka, M.Yamada, M.Sato.
Histone arginine methylation is a posttranslational modification linked to the regulation of gene transcription. Unlike other posttranslational modifications, methylation has generally been regarded as stable, and enzymes that demethylate histone arginine residues have not been identified. However, it has recently been shown that human peptidylarginine deiminase 4 (PAD4), a Ca(2+)-dependent enzyme previously known to convert arginine residues to citrulline in histones, can also convert monomethylated arginine residues to citrulline both in vivo and in vitro. Citrullination of histone arginine residues by the enzyme antagonizes methylation by histone arginine methyltransferases and is thus a novel posttranslational modification that regulates the level of histone arginine methylation and gene activity. Here we present the crystal structures of a Ca(2+)-bound PAD4 mutant in complex with three histone N-terminal peptides, each consisting of 10 amino acid residues that include one target arginine residue for the enzyme (H3/Arg-8, H3/Arg-17, and H4/Arg-3). To each histone N-terminal peptide, the enzyme induces a beta-turn-like bent conformation composed of five successive residues at the molecular surface near the active site cleft. The remaining five residues are highly disordered. The enzyme recognizes each peptide through backbone atoms of the peptide with a possible consensus recognition motif. The sequence specificity of the peptide recognized by this enzyme is thought to be fairly broad. These observations provide structural insights into target protein recognition by histone modification enzymes and illustrate how PAD4 can target multiple arginine sites in the histone N-terminal tails.
  Selected figure(s)  
Figure 2.
Fig. 2. Structure of Ca^2+-bound PAD4 (C645A) in complex with peptide H3-1. (A) Ribbon representation of the structure. Ca^2+ ions and the histone peptide are shown as yellow balls and as a green stick model, respectively. The N-terminal subdomains 1 (residues 1-118) and 2 (residues 119-300) and the C-terminal domain (residues 301-663) are colored green, blue, and red, respectively. The nuclear localization signal (NLS) region in the subdomain 1 is shown as a dotted line. (B Upper) Schematic representation of the structure shown in A. The colors of the N-terminal domain (subdomains 1 and 2) and the C-terminal domain are the same as in A. Dotted lines show hydrogen bonds that form a consensus recognition motif at the molecular surface near the active site. (B Lower) For reference, the structure of the Ca^2+-bound PAD4 (C645A) is shown.
Figure 3.
Fig. 3. Structures around the active sites of the Ca^2+-bound PAD4 (C645A) in complex with peptides H3-1, H3-2, H4, and BA. (Left) Ball-and-stick representation of the structures. The protein moiety is colored gray, and the peptides, H3-1 (A), H3-2 (B), H4 (C), and BA (D), are colored green, magenta, yellow, and cyan, respectively. Superimposed are F[o] - F[c] electron densities of the peptides, contoured at 2 . (Right) Schematic diagrams of the structures in Left. Dotted lines and green half-circles show hydrogen bonds and hydrophobic interactions, respectively. The structure of the complex with BA was drawn by using the refined coordinates deposited in the Protein Data Bank (accession code 1WDA).
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21377473 M.Unno, T.Kawasaki, H.Takahara, C.W.Heizmann, and K.Kizawa (2011).
Refined crystal structures of human Ca(2+)/Zn(2+)-binding S100A3 protein characterized by two disulfide bridges.
  J Mol Biol, 408, 477-490.
PDB codes: 3nsi 3nsk 3nsl 3nso
20201080 F.Andrade, E.Darrah, M.Gucek, R.N.Cole, A.Rosen, and X.Zhu (2010).
Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation.
  Arthritis Rheum, 62, 1630-1640.  
20192990 H.Uysal, K.S.Nandakumar, C.Kessel, S.Haag, S.Carlsen, H.Burkhardt, and R.Holmdahl (2010).
Antibodies to citrullinated proteins: molecular interactions and arthritogenicity.
  Immunol Rev, 233, 9.  
20648673 S.Shimoyama, A.Nagadoi, H.Tachiwana, M.Yamada, M.Sato, H.Kurumizaka, Y.Nishimura, and S.Akashi (2010).
Deimination stabilizes histone H2A/H2B dimers as revealed by electrospray ionization mass spectrometry.
  J Mass Spectrom, 45, 900-908.  
19040354 M.E.Stensland, S.Pollmann, O.Molberg, L.M.Sollid, and B.Fleckenstein (2009).
Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4.
  Biol Chem, 390, 99.  
19639564 M.Stensland, A.Holm, A.Kiehne, and B.Fleckenstein (2009).
Targeted analysis of protein citrullination using chemical modification and tandem mass spectrometry.
  Rapid Commun Mass Spectrom, 23, 2754-2762.  
20028143 Z.Ke, S.Wang, D.Xie, and Y.Zhang (2009).
Born-Oppenheimer ab initio QM/MM molecular dynamics simulations of the hydrolysis reaction catalyzed by protein arginine deiminase 4.
  J Phys Chem B, 113, 16705-16710.  
19507815 Z.Ke, Y.Zhou, P.Hu, S.Wang, D.Xie, and Y.Zhang (2009).
Active site cysteine is protonated in the PAD4 Michaelis complex: evidence from Born-Oppenheimer ab initio QM/MM molecular dynamics simulations.
  J Phys Chem B, 113, 12750-12758.  
18923545 A.A.Musse, E.Polverini, R.Raijmakers, and G.Harauz (2008).
Kinetics of human peptidylarginine deiminase 2 (hPAD2)--reduction of Ca2+ dependence by phospholipids and assessment of proposed inhibition by paclitaxel side chains.
  Biochem Cell Biol, 86, 437-447.  
17893996 A.Suzuki, R.Yamada, and K.Yamamoto (2007).
Citrullination by peptidylarginine deiminase in rheumatoid arthritis.
  Ann N Y Acad Sci, 1108, 323-339.  
17497940 B.Knuckley, M.Bhatia, and P.R.Thompson (2007).
Protein arginine deiminase 4: evidence for a reverse protonation mechanism.
  Biochemistry, 46, 6578-6587.  
17468392 F.Bachand (2007).
Protein arginine methyltransferases: from unicellular eukaryotes to humans.
  Eukaryot Cell, 6, 889-898.  
18489346 M.C.Méchin, M.Sebbag, J.Arnaud, R.Nachat, C.Foulquier, V.Adoue, F.Coudane, H.Duplan, A.M.Schmitt, S.Chavanas, M.Guerrin, G.Serre, and M.Simon (2007).
Update on peptidylarginine deiminases and deimination in skin physiology and severe human diseases.
  Int J Cosmet Sci, 29, 147-168.  
17984971 S.Lall (2007).
Primers on chromatin.
  Nat Struct Mol Biol, 14, 1110-1115.  
17882261 W.W.Yue, M.Hassler, S.M.Roe, V.Thompson-Vale, and L.H.Pearl (2007).
Insights into histone code syntax from structural and biochemical studies of CARM1 methyltransferase.
  EMBO J, 26, 4402-4412.
PDB codes: 2v74 2v7e
17374386 X.Cheng, and X.Zhang (2007).
Structural dynamics of protein lysine methylation and demethylation.
  Mutat Res, 618, 102-115.  
17083360 G.E.Rogers (2006).
Biology of the wool follicle: an excursion into a unique tissue interaction system waiting to be re-discovered.
  Exp Dermatol, 15, 931-949.  
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.