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5n0m

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Revision as of 07:34, 19 August 2020

hPAD4 crystal complex with BB-F-amidine

Structural highlights

5n0m is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	PADI4, PAD4, PADI5, PDI5 (HUMAN)
Activity:	Protein-arginine deiminase, with EC number 3.5.3.15
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PADI4_HUMAN] Genetic variations in PADI4 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM: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.^[1]

Function

[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.^[2] ^[3]

Publication Abstract from PubMed

Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in >100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated.

Development of a Selective Inhibitor of Protein Arginine Deiminase 2.,Muth A, Subramanian V, Beaumont E, Nagar M, Kerry P, McEwan P, Srinath H, Clancy K, Parelkar S, Thompson PR J Med Chem. 2017 Apr 13;60(7):3198-3211. doi: 10.1021/acs.jmedchem.7b00274. Epub , 2017 Mar 31. PMID:28328217^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003 Aug;34(4):395-402. PMID:12833157 doi:10.1038/ng1206
↑ Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T. Histone deimination antagonizes arginine methylation. Cell. 2004 Sep 3;118(5):545-53. PMID:15339660 doi:10.1016/j.cell.2004.08.020
↑ Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD, Coonrod SA. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004 Oct 8;306(5694):279-83. Epub 2004 Sep 2. PMID:15345777 doi:10.1126/science.1101400
↑ Muth A, Subramanian V, Beaumont E, Nagar M, Kerry P, McEwan P, Srinath H, Clancy K, Parelkar S, Thompson PR. Development of a Selective Inhibitor of Protein Arginine Deiminase 2. J Med Chem. 2017 Apr 13;60(7):3198-3211. doi: 10.1021/acs.jmedchem.7b00274. Epub , 2017 Mar 31. PMID:28328217 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00274

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5n0m"

@@ Line 1: / Line 1: @@
 ==hPAD4 crystal complex with BB-F-amidine==
-<StructureSection load='5n0m' size='340' side='right' caption='[[5n0m]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+<StructureSection load='5n0m' size='340' side='right'caption='[[5n0m]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5n0m]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N0M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5N0M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5n0m]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N0M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5N0M FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8HT:~{N}-[(1~{S})-1-(1~{H}-BENZIMIDAZOL-2-YL)-4-(2-FLUORANYLETHANIMIDOYLAMINO)BUTYL]-4-PHENYL-BENZAMIDE'>8HT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8HT:~{N}-[(1~{S})-1-(1~{H}-BENZIMIDAZOL-2-YL)-4-(2-FLUORANYLETHANIMIDOYLAMINO)BUTYL]-4-PHENYL-BENZAMIDE'>8HT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PADI4, PAD4, PADI5, PDI5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5n0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n0m OCA], [http://pdbe.org/5n0m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n0m RCSB], [http://www.ebi.ac.uk/pdbsum/5n0m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n0m ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5n0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n0m OCA], [http://pdbe.org/5n0m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n0m RCSB], [http://www.ebi.ac.uk/pdbsum/5n0m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n0m ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Protein-arginine deiminase]]
 [[Category: Beaumont, E]]

5n0m

From Proteopedia

Revision as of 07:34, 19 August 2020

hPAD4 crystal complex with BB-F-amidine

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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