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PDBsum entry 2dw5

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protein ligands metals links
Hydrolase PDB id
2dw5
Jmol
Contents
Protein chain
626 a.a. *
Ligands
SO4 ×3
BFB
Metals
_CA ×5
Waters ×150
* Residue conservation analysis
PDB id:
2dw5
Name: Hydrolase
Title: Crystal structure of human peptidylarginine deiminase 4 in c with n-alpha-benzoyl-n5-(2-fluoro-1-iminoethyl)-l-ornithine
Structure: Protein-arginine deiminase type-4. Chain: a. Synonym: protein-arginine deiminase type iv, peptidylargini deiminase iv, hl-60 pad. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: padi4, padi5, pdi5. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
Resolution:
2.30Å     R-factor:   0.200     R-free:   0.252
Authors: Y.Luo,K.Arita,M.Sato,P.R.Thompson
Key ref:
Y.Luo et al. (2006). Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry, 45, 11727-11736. PubMed id: 17002273 DOI: 10.1021/bi061180d
Date:
04-Aug-06     Release date:   17-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9UM07  (PADI4_HUMAN) -  Protein-arginine deiminase type-4
Seq:
Struc:
 
Seq:
Struc:
663 a.a.
626 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.5.3.15  - Protein-arginine deiminase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein L-arginine + H2O = protein L-citrulline + NH3
Protein L-arginine
Bound ligand (Het Group name = BFB)
matches with 56.52% 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: 10.1021/bi061180d Biochemistry 45:11727-11736 (2006)
PubMed id: 17002273  
 
 
Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization.
Y.Luo, K.Arita, M.Bhatia, B.Knuckley, Y.H.Lee, M.R.Stallcup, M.Sato, P.R.Thompson.
 
  ABSTRACT  
 
Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins to citrulline. Recently, we reported the synthesis and characterization of F-amidine, a potent and bioavailable irreversible inactivator of PAD4. Herein, we report our efforts to identify the steric and leaving group requirements for F-amidine-induced PAD4 inactivation, the structure of the PAD4-F-amidine x calcium complex, and in vivo studies with N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a PAD4 inactivator with enhanced potency. The PAD4 inactivators described herein will be useful pharmacological probes in characterizing the incompletely defined physiological role(s) of this enzyme. In addition, they represent potential lead compounds for the treatment of rheumatoid arthritis because a growing body of evidence supports a role for PAD4 in the onset and progression of this chronic autoimmune disorder.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20706768 J.L.Slack, C.P.Causey, and P.R.Thompson (2011).
Protein arginine deiminase 4: a target for an epigenetic cancer therapy.
  Cell Mol Life Sci, 68, 709-720.  
20607165 K.L.Bicker, O.Obianyo, H.L.Rust, and P.R.Thompson (2011).
A combinatorial approach to characterize the substrate specificity of protein arginine methyltransferase 1.
  Mol Biosyst, 7, 48-51.  
20014086 B.Knuckley, C.P.Causey, P.J.Pellechia, P.F.Cook, and P.R.Thompson (2010).
Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that general acid catalysis promotes efficient inactivation.
  Chembiochem, 11, 161-165.  
20740228 B.Knuckley, J.E.Jones, D.A.Bachovchin, J.Slack, C.P.Causey, S.J.Brown, H.Rosen, B.F.Cravatt, and P.R.Thompson (2010).
A fluopol-ABPP HTS assay to identify PAD inhibitors.
  Chem Commun (Camb), 46, 7175-7177.  
20036411 J.E.Jones, C.P.Causey, L.Lovelace, B.Knuckley, H.Flick, L.Lebioda, and P.R.Thompson (2010).
Characterization and inactivation of an agmatine deiminase from Helicobacter pylori.
  Bioorg Chem, 38, 62-73.
PDB code: 3hvm
20480486 O.Obianyo, C.P.Causey, T.C.Osborne, J.E.Jones, Y.H.Lee, M.R.Stallcup, and P.R.Thompson (2010).
A chloroacetamidine-based inactivator of protein arginine methyltransferase 1: design, synthesis, and in vitro and in vivo evaluation.
  Chembiochem, 11, 1219-1223.  
20553633 P.Mangat, N.Wegner, P.J.Venables, and J.Potempa (2010).
Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis?
  Arthritis Res Ther, 12, 209.  
18603028 B.C.Smith, and J.M.Denu (2009).
Chemical mechanisms of histone lysine and arginine modifications.
  Biochim Biophys Acta, 1789, 45-57.  
19153223 Y.Wang, M.Li, S.Stadler, S.Correll, P.Li, D.Wang, R.Hayama, L.Leonelli, H.Han, S.A.Grigoryev, C.D.Allis, and S.A.Coonrod (2009).
Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation.
  J Cell Biol, 184, 205-213.  
19678909 Z.Baka, E.Buzás, and G.Nagy (2009).
Rheumatoid arthritis and smoking: putting the pieces together.
  Arthritis Res Ther, 11, 238.  
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.  
17964793 B.Knuckley, Y.Luo, and P.R.Thompson (2008).
Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors.
  Bioorg Med Chem, 16, 739-745.  
19587776 C.P.Causey, and P.R.Thompson (2008).
An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 4 (PAD4).
  Tetrahedron Lett, 49, 4383-4385.  
  19727327 D.B.Berkowitz, K.R.Karukurichi, R.de la Salud-Bea, D.L.Nelson, and C.D.McCune (2008).
Use of Fluorinated Functionality in Enzyme Inhibitor Development: Mechanistic and Analytical Advantages.
  J Fluor Chem, 129, 731-742.  
18227806 D.D.Wood, C.A.Ackerley, B.Brand, L.Zhang, R.Raijmakers, F.G.Mastronardi, and M.A.Moscarello (2008).
Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities.
  Lab Invest, 88, 354-364.  
18499678 H.Yao, P.Li, B.J.Venters, S.Zheng, P.R.Thompson, B.F.Pugh, and Y.Wang (2008).
Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis.
  J Biol Chem, 283, 20060-20068.  
18505818 P.Li, H.Yao, Z.Zhang, M.Li, Y.Luo, P.R.Thompson, D.S.Gilmour, and Y.Wang (2008).
Regulation of p53 target gene expression by peptidylarginine deiminase 4.
  Mol Cell Biol, 28, 4745-4758.  
18482699 T.W.Linsky, A.F.Monzingo, E.M.Stone, J.D.Robertus, and W.Fast (2008).
Promiscuous partitioning of a covalent intermediate common in the pentein superfamily.
  Chem Biol, 15, 467-475.
PDB code: 3bpb
17497940 B.Knuckley, M.Bhatia, and P.R.Thompson (2007).
Protein arginine deiminase 4: evidence for a reverse protonation mechanism.
  Biochemistry, 46, 6578-6587.  
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.  
17342184 R.J.Klose, and Y.Zhang (2007).
Regulation of histone methylation by demethylimination and demethylation.
  Nat Rev Mol Cell Biol, 8, 307-318.  
17090024 Y.Luo, B.Knuckley, M.Bhatia, P.J.Pellechia, and P.R.Thompson (2006).
Activity-based protein profiling reagents for protein arginine deiminase 4 (PAD4): synthesis and in vitro evaluation of a fluorescently labeled probe.
  J Am Chem Soc, 128, 14468-14469.  
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.