Target Information
| Target General Information | Top | |||||
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| Target ID |
T28052
(Former ID: TTDNR00703)
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| Target Name |
Lysine-specific demethylase 5A (KDM5A)
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| Synonyms |
Retinoblastoma-binding protein 2; RBP2; RBBP2; RBBP-2; Jumonji/ARID domain-containing protein 1A; JARID1A; Histone demethylase JARID1A
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| Gene Name |
KDM5A
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| Target Type |
Patented-recorded target
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| Function |
Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif. May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1. Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells. Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code.
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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 |
MAGVGPGGYAAEFVPPPECPVFEPSWEEFTDPLSFIGRIRPLAEKTGICKIRPPKDWQPP
FACEVKSFRFTPRVQRLNELEAMTRVRLDFLDQLAKFWELQGSTLKIPVVERKILDLYAL SKIVASKGGFEMVTKEKKWSKVGSRLGYLPGKGTGSLLKSHYERILYPYELFQSGVSLMG VQMPNLDLKEKVEPEVLSTDTQTSPEPGTRMNILPKRTRRVKTQSESGDVSRNTELKKLQ IFGAGPKVVGLAMGTKDKEDEVTRRRKVTNRSDAFNMQMRQRKGTLSVNFVDLYVCMFCG RGNNEDKLLLCDGCDDSYHTFCLIPPLPDVPKGDWRCPKCVAEECSKPREAFGFEQAVRE YTLQSFGEMADNFKSDYFNMPVHMVPTELVEKEFWRLVSSIEEDVIVEYGADISSKDFGS GFPVKDGRRKILPEEEEYALSGWNLNNMPVLEQSVLAHINVDISGMKVPWLYVGMCFSSF CWHIEDHWSYSINYLHWGEPKTWYGVPSHAAEQLEEVMRELAPELFESQPDLLHQLVTIM NPNVLMEHGVPVYRTNQCAGEFVVTFPRAYHSGFNQGYNFAEAVNFCTADWLPIGRQCVN HYRRLRRHCVFSHEELIFKMAADPECLDVGLAAMVCKELTLMTEEETRLRESVVQMGVLM SEEEVFELVPDDERQCSACRTTCFLSALTCSCNPERLVCLYHPTDLCPCPMQKKCLRYRY PLEDLPSLLYGVKVRAQSYDTWVSRVTEALSANFNHKKDLIELRVMLEDAEDRKYPENDL FRKLRDAVKEAETCASVAQLLLSKKQKHRQSPDSGRTRTKLTVEELKAFVQQLFSLPCVI SQARQVKNLLDDVEEFHERAQEAMMDETPDSSKLQMLIDMGSSLYVELPELPRLKQELQQ ARWLDEVRLTLSDPQQVTLDVMKKLIDSGVGLAPHHAVEKAMAELQELLTVSERWEEKAK VCLQARPRHSVASLESIVNEAKNIPAFLPNVLSLKEALQKAREWTAKVEAIQSGSNYAYL EQLESLSAKGRPIPVRLEALPQVESQVAAARAWRERTGRTFLKKNSSHTLLQVLSPRTDI GVYGSGKNRRKKVKELIEKEKEKDLDLEPLSDLEEGLEETRDTAMVVAVFKEREQKEIEA MHSLRAANLAKMTMVDRIEEVKFCICRKTASGFMLQCELCKDWFHNSCVPLPKSSSQKKG SSWQAKEVKFLCPLCMRSRRPRLETILSLLVSLQKLPVRLPEGEALQCLTERAMSWQDRA RQALATDELSSALAKLSVLSQRMVEQAAREKTEKIISAELQKAAANPDLQGHLPSFQQSA FNRVVSSVSSSPRQTMDYDDEETDSDEDIRETYGYDMKDTASVKSSSSLEPNLFCDEEIP IKSEEVVTHMWTAPSFCAEHAYSSASKSCSQGSSTPRKQPRKSPLVPRSLEPPVLELSPG AKAQLEELMMVGDLLEVSLDETQHIWRILQATHPPSEDRFLHIMEDDSMEEKPLKVKGKD SSEKKRKRKLEKVEQLFGEGKQKSKELKKMDKPRKKKLKLGADKSKELNKLAKKLAKEEE RKKKKEKAAAAKVELVKESTEKKREKKVLDIPSKYDWSGAEESDDENAVCAAQNCQRPCK DKVDWVQCDGGCDEWFHQVCVGVSPEMAENEDYICINCAKKQGPVSPGPAPPPSFIMSYK LPMEDLKETS 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: Alpha-ketoglutaric acid | Ligand Info | |||||
| Structure Description | A High Resolution Structure of a Linked KDM5A Jmj Domain with Alpha-Ketoglutarate | PDB:5IVB | ||||
| Method | X-ray diffraction | Resolution | 1.39 Å | Mutation | No | [13] |
| PDB Sequence |
EFVPPPECPV
21 FEPSWEEFTD31 PLSFIGRIRP41 LAEKTGICKI51 RPPKDWQPPF61 ACEVKSFRFT 71 PRVQRLNELE81 AMTEQAVREY361 TLQSFGEMAD371 NFKSDYFNMP381 VHMVPTELVE 391 KEFWRLVSSI401 EEDVIVEYGA411 DISSKDFGSG421 FPVKDGRRKI431 LPEEEEYALS 441 GWNLNNMPVL451 EKVPWLYVGM475 CFSSFCWHIE485 DHWSYSINYL495 HWGEPKTWYG 505 VPSHAAEQLE515 EVMRELAPEL525 FESQPDLLHQ535 LVTIMNPNVL545 MEHGVPVYRT 555 NQCAGEFVVT565 FPRAYHSGFN575 QGYNFAEAVN585 FCT
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: GSK-J1 | Ligand Info | |||||
| Structure Description | LINKED KDM5A JMJ DOMAIN BOUND TO THE INHIBITOR GSK-J1 | PDB:6DQ4 | ||||
| Method | X-ray diffraction | Resolution | 1.39 Å | Mutation | No | [14] |
| PDB Sequence |
AEFVPPPECP
20 VFEPSWEEFT30 DPLSFIGRIR40 PLAEKTGICK50 IRPPKDWQPP60 FACEVKSFRF 70 TPRVQRLNEL80 EAMTRPREAF352 GFEQAVREYT362 LQSFGEMADN372 FKSDYFNMPV 382 HMVPTELVEK392 EFWRLVSSIE402 EDVIVEYGAD412 ISSKDFGSGF422 PVKDGRRKIL 432 PEEEEYALSG442 WNLNNMPVLE452 QSVLAHINVM466 KVPWLYVGMC476 FSSFCWHIED 486 HWSYSINYLH496 WGEPKTWYGV506 PSHAAEQLEE516 VMRELAPELF526 ESQPDLLHQL 536 VTIMNPNVLM546 EHGVPVYRTN556 QCAGEFVVTF566 PRAYHSGFNQ576 GYNFAEAVNF 586 CT
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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).
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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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 | 2.02E-04 |
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| Closeness centrality | 1.86E-01 | Radiality | 1.31E+01 | Clustering coefficient | 5.00E-01 |
| Neighborhood connectivity | 1.50E+01 | Topological coefficient | 3.35E-01 | 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 | Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J Biol Chem. 2013 Mar 29;288(13):9408-17. | |||||
| REF 2 | Histone demethylase inhibitors. US9714230. | |||||
| REF 3 | Histone demethylase inhibitors. US9611221. | |||||
| REF 4 | Histone demethylase inhibitors. US10179769. | |||||
| REF 5 | Histone demethylase inhibitors. US10173996. | |||||
| REF 6 | Histone demethylase inhibitors. US9725441. | |||||
| REF 7 | Histone demethylase inhibitors. US10040779. | |||||
| REF 8 | Histone demethylase inhibitors. US9617242. | |||||
| REF 9 | Histone demethylase inhibitors. US9738637. | |||||
| REF 10 | IRE-1 inhibitors | |||||
| REF 11 | Histone demethylase inhibitors. US10174026. | |||||
| REF 12 | Histone demethylase inhibitors. US9604961. | |||||
| REF 13 | Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds. Cell Chem Biol. 2016 Jul 21;23(7):769-781. | |||||
| REF 14 | Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A. J Med Chem. 2018 Dec 13;61(23):10588-10601. | |||||
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