Target Information
| Target General Information | Top | |||||
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| Target ID |
T18904
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| Target Name |
Lysine-specific demethylase 4A (KDM4A)
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| Synonyms |
KIAA0677; Jumonji domain-containing protein 2A; JmjC domain-containing histone demethylation protein 3A; JMJD2A; JMJD2; JHDM3A
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| Gene Name |
KDM4A
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively.
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| BioChemical Class |
Paired donor oxygen oxidoreductase
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| UniProt ID | ||||||
| EC Number |
EC 1.14.11.-
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| Sequence |
MASESETLNPSARIMTFYPTMEEFRNFSRYIAYIESQGAHRAGLAKVVPPKEWKPRASYD
DIDDLVIPAPIQQLVTGQSGLFTQYNIQKKAMTVREFRKIANSDKYCTPRYSEFEELERK YWKNLTFNPPIYGADVNGTLYEKHVDEWNIGRLRTILDLVEKESGITIEGVNTPYLYFGM WKTSFAWHTEDMDLYSINYLHFGEPKSWYSVPPEHGKRLERLAKGFFPGSAQSCEAFLRH KMTLISPLMLKKYGIPFDKVTQEAGEFMITFPYGYHAGFNHGFNCAESTNFATRRWIEYG KQAVLCSCRKDMVKISMDVFVRKFQPERYKLWKAGKDNTVIDHTLPTPEAAEFLKESELP PRAGNEEECPEEDMEGVEDGEEGDLKTSLAKHRIGTKRHRVCLEIPQEVSQSELFPKEDL SSEQYEMTECPAALAPVRPTHSSVRQVEDGLTFPDYSDSTEVKFEELKNVKLEEEDEEEE QAAAALDLSVNPASVGGRLVFSGSKKKSSSSLGSGSSRDSISSDSETSEPLSCRAQGQTG VLTVHSYAKGDGRVTVGEPCTRKKGSAARSFSERELAEVADEYMFSLEENKKSKGRRQPL SKLPRHHPLVLQECVSDDETSEQLTPEEEAEETEAWAKPLSQLWQNRPPNFEAEKEFNET MAQQAPHCAVCMIFQTYHQVEFGGFNQNCGNASDLAPQKQRTKPLIPEMCFTSTGCSTDI NLSTPYLEEDGTSILVSCKKCSVRVHASCYGVPPAKASEDWMCSRCSANALEEDCCLCSL RGGALQRANDDRWVHVSCAVAILEARFVNIAERSPVDVSKIPLPRFKLKCIFCKKRRKRT AGCCVQCSHGRCPTAFHVSCAQAAGVMMQPDDWPFVVFITCFRHKIPNLERAKGALQSIT AGQKVISKHKNGRFYQCEVVRLTTETFYEVNFDDGSFSDNLYPEDIVSQDCLQFGPPAEG EVVQVRWTDGQVYGAKFVASHPIQMYQVEFEDGSQLVVKRDDVYTLDEELPKRVKSRLSV ASDMRFNEIFTEKEVKQEKKRQRVINSRYREDYIEPALYRAIME Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| 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: Pyruvic acid | Ligand Info | |||||
| Structure Description | Crystal structure of human JMJD2A in complex with pyruvate | PDB:5FYI | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [3] |
| PDB Sequence |
ESETLNPSAR
13 IMTFYPTMEE23 FRNFSRYIAY33 IESQGAHRAG43 LAKVVPPKEW53 KPRASYDDID 63 DLVIPAPIQQ73 LVTGQSGLFT83 QYNIQKKAMT93 VREFRKIANS103 DKYCTPRYSE 113 FEELERKYWK123 NLTFNPPIYG133 ADVNGTLYEK143 HVDEWNIGRL153 RTILDLVEKE 163 SGITIEGVNT173 PYLYFGMWKT183 SFAWHTEDMD193 LYSINYLHFG203 EPKSWYSVPP 213 EHGKRLERLA223 KGFFPGSAQS233 CEAFLRHKMT243 LISPLMLKKY253 GIPFDKVTQE 263 AGEFMITFPY273 GYHAGFNHGF283 NCAESTNFAT293 RRWIEYGKQA303 VLCSCRKDMV 313 KISMDVFVRK323 FQPERYKLWK333 AGKDNTVIDH343 TLPTPEAAEF353 L |
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| Ligand Name: Fumaric acid | Ligand Info | |||||
| Structure Description | Crystal structure of human JMJD2A in complex with succinate | PDB:5FYC | ||||
| Method | X-ray diffraction | Resolution | 2.26 Å | Mutation | No | [4] |
| PDB Sequence |
LNPSARIMTF
17 YPTMEEFRNF27 SRYIAYIESQ37 GAHRAGLAKV47 VPPKEWKPRA57 SYDDIDDLVI 67 PAPIQQLVTG77 QSGLFTQYNI87 QKKAMTVREF97 RKIANSDKYC107 TPRYSEFEEL 117 ERKYWKNLTF127 NPPIYGADVN137 GTLYEKHVDE147 WNIGRLRTIL157 DLVEKESGIT 167 IEGVNTPYLY177 FGMWKTSFAW187 HTEDMDLYSI197 NYLHFGEPKS207 WYSVPPEHGK 217 RLERLAKGFF227 PGSAQSCEAF237 LRHKMTLISP247 LMLKKYGIPF257 DKVTQEAGEF 267 MITFPYGYHA277 GFNHGFNCAE287 STNFATRRWI297 EYGKQAVLCS307 CRKDMVKISM 317 DVFVRKFQPE327 RYKLWKAGKD337 NTVIDHTLPT347 PEAAEF
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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).
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
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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| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 3.46E-05 |
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| Closeness centrality | 2.03E-01 | Radiality | 1.35E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.73E+01 | Topological coefficient | 2.71E-01 | Eccentricity | 11 |
| 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-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | KDM4 histone demethylase inhibitors for anti-cancer agents: a patent review.Expert Opin Ther Pat. 2015 Feb;25(2):135-44. | |||||
| REF 2 | LSD1 inhibitors: a patent review (2010-2015).Expert Opin Ther Pat. 2016 May;26(5):565-80. | |||||
| REF 3 | Crystal Structure of Human Jmjd2A in Complex with Pyruvate | |||||
| REF 4 | Crystal Structure of Human Jmjd2A in Complex with Succinate | |||||
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