Target Information
| Target General Information | Top | |||||
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| Target ID |
T50429
(Former ID: TTDI03455)
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| Target Name |
Peptidyl arginine deiminase type IV (PADI4)
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| Synonyms |
Protein-arginine deiminase type-4; Protein-arginine deiminase type IV; Peptidylarginine deiminase IV; PDI5; PADI5; PAD4; HL-60 PAD
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| Gene Name |
PADI4
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1. Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance.
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| BioChemical Class |
Carbon-nitrogen hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.3.15
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| Sequence |
MAQGTLIRVTPEQPTHAVCVLGTLTQLDICSSAPEDCTSFSINASPGVVVDIAHGPPAKK
KSTGSSTWPLDPGVEVTLTMKVASGSTGDQKVQISYYGPKTPPVKALLYLTGVEISLCAD ITRTGKVKPTRAVKDQRTWTWGPCGQGAILLVNCDRDNLESSAMDCEDDEVLDSEDLQDM SLMTLSTKTPKDFFTNHTLVLHVARSEMDKVRVFQATRGKLSSKCSVVLGPKWPSHYLMV PGGKHNMDFYVEALAFPDTDFPGLITLTISLLDTSNLELPEAVVFQDSVVFRVAPWIMTP NTQPPQEVYACSIFENEDFLKSVTTLAMKAKCKLTICPEEENMDDQWMQDEMEIGYIQAP HKTLPVVFDSPRNRGLKEFPIKRVMGPDFGYVTRGPQTGGISGLDSFGNLEVSPPVTVRG KEYPLGRILFGDSCYPSNDSRQMHQALQDFLSAQQVQAPVKLYSDWLSVGHVDEFLSFVP APDRKGFRLLLASPRSCYKLFQEQQNEGHGEALLFEGIKKKKQQKIKNILSNKTLREHNS FVERCIDWNRELLKRELGLAESDIIDIPQLFKLKEFSKAEAFFPNMVNMLVLGKHLGIPK PFGPVINGRCCLEEKVCSLLEPLGLQCTFINDFFTYHIRHGEVHCGTNVRRKPFSFKWWN MVP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: N-[(1S)-4-[(1-amino-2-fluoroethylidene)amino]-1-(1H-benzimidazol-2-yl)butyl]-4-phenylbenzamide | Ligand Info | |||||
| Structure Description | hPAD4 crystal complex with BB-F-amidine | PDB:5N0M | ||||
| Method | X-ray diffraction | Resolution | 2.18 Å | Mutation | Yes | [4] |
| PDB Sequence |
QGTLIRVTPE
12 QPTHAVCVLG22 TLTQLDICSS32 APEDCTSFSI42 NASPGVVVDI52 AHSTWPLDPG 73 VEVTLTMKAA83 SGSTGDQKVQ93 ISYYGPKTPP103 VKALLYLTAV113 EISLCADITR 123 TGKVKRTWTW141 GPCGQGAILL151 VNCDRDNLES161 SAMDCEDDEV171 LDSEDLQDMS 181 LMTLSTKTPK191 DFFTNHTLVL201 HVARSEMDKV211 RVFQATKCSV227 VLGPKWPSHY 237 LMVPGGKHNM247 DFYVEALAFP257 DTDFPGLITL267 TISLLDTSNL277 ELPEAVVFQD 287 SVVFRVAPWI297 MTPNTQPPQE307 VYACSIFENE317 DFLKSVTTLA327 MKAKCKLTIC 337 PEEENMDDQW347 MQDEMEIGYI357 QAPHKTLPVV367 FDSPRNRGLK377 EFPIKRVMGP 387 DFGYVTRGPQ397 TGGISGLDSF407 GNLEVSPPVT417 VRGKEYPLGR427 ILFGDSCYPS 437 NDSRQMHQAL447 QDFLSAQQVQ457 APVKLYSDWL467 SVGHVDEFLS477 FVPAPDRKGF 487 RLLLASPRSC497 YKLFQEQQNE507 GHGEALLFEG517 IKKKKQQKIK527 NILSNKTLRE 537 HNSFVERCID547 WNRELLKREL557 GLAESDIIDI567 PQLFKLKEFS577 KAEAFFPNMV 587 NMLVLGKHLG597 IPKPFGPVIN607 GRCCLEEKVC617 SLLEPLGLQC627 TFINDFFTYH 637 IRHGEVHCGT647 NVRRKPFSFK657 WWNMVP
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| Ligand Name: N-[(1S)-4-[(2-fluoro-1-iminoethyl)amino]-1-(4-methoxy-1-methyl-1H-benzimidazol-2-yl)butyl]-2,3-dihydro-3-oxo-1H-isoindole-4-carboxamide | Ligand Info | |||||
| Structure Description | hPAD4 crystal complex with AFM-30a | PDB:5N0Y | ||||
| Method | X-ray diffraction | Resolution | 2.23 Å | Mutation | Yes | [4] |
| PDB Sequence |
QGTLIRVTPE
12 QPTHAVCVLG22 TLTQLDICSS32 APEDCTSFSI42 NASPGVVVDI52 AHSTWPLDPG 73 VEVTLTMKAA83 SGSTGDQKVQ93 ISYYGPKTPP103 VKALLYLTAV113 EISLCADITR 123 TGKVRTWTWG142 PCGQGAILLV152 NCDRDNLESS162 AMDCEDDEVL172 DSEDLQDMSL 182 MTLSTKTPKD192 FFTNHTLVLH202 VARSEMDKVR212 VFQATKCSVV228 LGPKWPSHYL 238 MVPGGKHNMD248 FYVEALAFPD258 TDFPGLITLT268 ISLLDTSNLE278 LPEAVVFQDS 288 VVFRVAPWIM298 TPNTQPPQEV308 YACSIFENED318 FLKSVTTLAM328 KAKCKLTICP 338 EEENMDDQWM348 QDEMEIGYIQ358 APHKTLPVVF368 DSPRNRGLKE378 FPIKRVMGPD 388 FGYVTRGPQT398 GGISGLDSFG408 NLEVSPPVTV418 RGKEYPLGRI428 LFGDSCYPSN 438 DSRQMHQALQ448 DFLSAQQVQA458 PVKLYSDWLS468 VGHVDEFLSF478 VPAPDRKGFR 488 LLLASPRSCY498 KLFQEQQNEG508 HGEALLFEGI518 KKKKQQKIKN528 ILSNKTLREH 538 NSFVERCIDW548 NRELLKRELG558 LAESDIIDIP568 QLFKLKEFSK578 AEAFFPNMVN 588 MLVLGKHLGI598 PKPFGPVING608 RCCLEEKVCS618 LLEPLGLQCT628 FINDFFTYHI 638 RHGEVHCGTN648 VRRKPFSFKW658 WNMVP
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ASP344
4.815
GLN346
3.902
TRP347
3.184
GLN349
3.834
ASP350
2.735
ARG372
4.035
ARG374
3.231
GLY403
4.490
SER406
3.842
GLY408
3.775
VAL469
3.553
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 2.15E-01 | Radiality | 1.38E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.66E+02 | Topological coefficient | 1.00E+00 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem Commun (Camb). 2010 Oct 14;46(38):7175-7. | |||||
| REF 2 | Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. J Am Chem Soc. 2015 Mar 18;137(10):3616-21. | |||||
| REF 3 | Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation. Bioorg Med Chem. 2014 Feb 15;22(4):1362-9. | |||||
| REF 4 | Development of a Selective Inhibitor of Protein Arginine Deiminase 2. J Med Chem. 2017 Apr 13;60(7):3198-3211. | |||||
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