peptidyl arginine deiminase 4

Target id: 2877

Nomenclature: peptidyl arginine deiminase 4

Family: 3.5.3.15 Peptidyl arginine deiminases (PADI)

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     peptidyl arginine deiminase 4 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 663 1p36.13 PADI4 peptidyl arginine deiminase 4
Mouse - 666 4 E1 Padi4 peptidyl arginine deiminase, type IV
Rat - 666 5q36 Padi4 peptidyl arginine deiminase 4
Previous and Unofficial Names
peptidyl arginine deiminase, type IV | peptidyl arginine deiminase
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human peptidylarginine deiminase 4 in complex with o-F-amidine.
PDB Id:  3B1U
Ligand:  o-F-amidine
Resolution:  2.1Å
Species:  Human
References:  1
Enzyme Reaction
EC Number: 3.5.3.15 protein L-arginine + H2O <=> protein L-citrulline + NH3

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
o-F-amidine Hs Irreversible inhibition 5.7 pIC50 1
pIC50 5.7 (IC50 1.9x10-6 M) [1]
streptonigrin N/A Inhibition 5.6 pIC50 7
pIC50 5.6 (IC50 2.5x10-6 M) [7]
compound 3 [PMID: 24440480] N/A Irreversible inhibition - - 2
[2]
Description: Kinact/KI = 5.7x103 M-1 min-1
compound 14b [PMID: 25742366] Hs Irreversible inhibition - - 6
[6]
Description: Kinact/KI = 1.46x103 M-1 min-1
Cl-amidine Hs Inhibition - - 6
[6]
Description: Kinact/KI = 1.77x103 M-1 min-1
View species-specific inhibitor tables
Immunopharmacology Comments
PADI4 is essential for neutrophil extracellular trap (NET) formation (NETosis) in pathogen elimination. PADI4-formed NETs containing hypercitrullinated histone H3 are detected in several systemic autoimmune diseases, including lupus and rheumatoid arthritis [3]. PADI4 polymorphisms are associated with rheumatoid arthritis, most significantly in diverse Asian populations [4-5,8-9,11], and PADI4 knockout mice exhibit decreased severity of experimental autoimmune arthritis,[10].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  innate immune response (GO:0045087) IEA
References: 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Rheumatoid arthritis
Disease Ontology: DOID:7148
OMIM: 180300

References

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1. Causey CP, Jones JE, Slack JL, Kamei D, Jones LE, Subramanian V, Knuckley B, Ebrahimi P, Chumanevich AA, Luo Y et al.. (2011) The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. J. Med. Chem.54 (19): 6919-35. [PMID:21882827]

2. Dreyton CJ, Anderson ED, Subramanian V, Boger DL, Thompson PR. (2014) Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation. Bioorg. Med. Chem.22 (4): 1362-9. [PMID:24440480]

3. Fuhrmann J, Thompson PR. (2016) Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chem. Biol.11 (3): 654-68. [PMID:26686581]

4. Gong LL, Chang J, Yang YM. (2016) Association between peptidyl arginine deiminase 4 (PADI4)-104C/T polymorphism and rheumatoid arthritis: a meta-analysis in the Chinese population. Genet. Mol. Res.15 (3). [PMID:27706751]

5. Hisa K, Yanagimachi MD, Naruto T, Miyamae T, Kikuchi M, Hara R, Imagawa T, Yokota S, Mori M. (2017) PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis. PLoS ONE12 (2): e0171961. [PMID:28182665]

6. Jamali H, Khan HA, Stringer JR, Chowdhury S, Ellman JA. (2015) Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. J. Am. Chem. Soc.137 (10): 3616-21. [PMID:25742366]

7. Knuckley B, Jones JE, Bachovchin DA, Slack J, Causey CP, Brown SJ, Rosen H, Cravatt BF, Thompson PR. (2010) A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem. Commun. (Camb.)46 (38): 7175-7. [PMID:20740228]

8. Shamsian E, Azarian M, Akhlaghi M, Samaei M, Jamshidi AR, Assar S, Shakiba Y, Gharibdoost F, Nourijelyani K, Mahmoudi M. (2016) PADI4 Polymorphisms in Iranian Patients with Rheumatoid Arthritis. Acta Reumatol Port41 (4): 338-343. [PMID:27182695]

9. Song ST, Kim SS, Kim JY, Lee SY, Kim K, Kwon IS, Kim JN, Park WH, Yoo IS, Yoo SJ et al.. (2016) Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases. Lung194 (5): 745-53. [PMID:27372294]

10. Suzuki A, Kochi Y, Shoda H, Seri Y, Fujio K, Sawada T, Yamada R, Yamamoto K. (2016) Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Musculoskelet Disord17: 205. [PMID:27150598]

11. Too CL, Murad S, Dhaliwal JS, Larsson P, Jiang X, Ding B, Alfredsson L, Klareskog L, Padyukov L. (2012) Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis. Arthritis Res. Ther.14 (6): R250. [PMID:23164236]

How to cite this page

3.5.3.15 Peptidyl arginine deiminases (PADI): peptidyl arginine deiminase 4. Last modified on 21/03/2017. Accessed on 23/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2877.