2dw5

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[[Image:2dw5.gif|left|200px]]
 
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{{Structure
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==Crystal structure of human peptidylarginine deiminase 4 in complex with N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-L-ornithine amide==
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|PDB= 2dw5 |SIZE=350|CAPTION= <scene name='initialview01'>2dw5</scene>, resolution 2.30&Aring;
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<StructureSection load='2dw5' size='340' side='right'caption='[[2dw5]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=BFB:N-[(1S)-1-(AMINOCARBONYL)-4-(ETHANIMIDOYLAMINO)BUTYL]BENZAMIDE'>BFB</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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<table><tr><td colspan='2'>[[2dw5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DW5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2DW5 FirstGlance]. <br>
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-arginine_deiminase Protein-arginine deiminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.15 3.5.3.15] </span>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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|GENE= PADI4, PADI5, PDI5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BFB:N-[(1S)-1-(AMINOCARBONYL)-4-(ETHANIMIDOYLAMINO)BUTYL]BENZAMIDE'>BFB</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2dw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2dw5 OCA], [https://pdbe.org/2dw5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2dw5 RCSB], [https://www.ebi.ac.uk/pdbsum/2dw5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2dw5 ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2dew|2DEW]], [[2dex|2DEX]], [[2dey|2DEY]], [[1wd8|1WD8]], [[1wd9|1WD9]], [[1wda|1WDA]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2dw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2dw5 OCA], [http://www.ebi.ac.uk/pdbsum/2dw5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2dw5 RCSB]</span>
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== Disease ==
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}}
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[https://www.uniprot.org/uniprot/PADI4_HUMAN PADI4_HUMAN] Genetic variations in PADI4 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM:[https://omim.org/entry/180300 180300]. It is a systemic inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Note=Could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context.<ref>PMID:12833157</ref>
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== Function ==
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'''Crystal structure of human peptidylarginine deiminase 4 in complex with N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-L-ornithine amide'''
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[https://www.uniprot.org/uniprot/PADI4_HUMAN PADI4_HUMAN] Catalyzes the citrullination/deimination of arginine residues of proteins. Citrullinates histone H3 at 'Arg-8' and/or 'Arg-17' and histone H4 at 'Arg-3', which prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.<ref>PMID:15339660</ref> <ref>PMID:15345777</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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==Overview==
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dw/2dw5_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2dw5 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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.
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.
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==About this Structure==
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Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization.,Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR Biochemistry. 2006 Oct 3;45(39):11727-36. PMID:17002273<ref>PMID:17002273</ref>
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2DW5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2DW5 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization., Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR, Biochemistry. 2006 Oct 3;45(39):11727-36. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17002273 17002273]
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</div>
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<div class="pdbe-citations 2dw5" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein-arginine deiminase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Arita K]]
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[[Category: Arita, K.]]
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[[Category: Luo Y]]
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[[Category: Luo, Y.]]
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[[Category: Sato M]]
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[[Category: Sato, M.]]
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[[Category: Thompson PR]]
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[[Category: Thompson, P R.]]
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[[Category: protein-inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:40:22 2008''
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Current revision

Crystal structure of human peptidylarginine deiminase 4 in complex with N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-L-ornithine amide

PDB ID 2dw5

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