Target Information
| Target General Information | Top | |||||
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| Target ID |
T81780
(Former ID: TTDR01334)
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| Target Name |
Ubiquitin-activating enzyme E1 (UBAE1)
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| Synonyms |
Ubiquitin-like modifier-activating enzyme 1; UBE1; Protein A1S9; A1S9T
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| Gene Name |
UBA1
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Leukaemia [ICD-11: 2A60-2B33] | |||||
| Function |
Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system. Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Essential for the formation of radiation-induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites.
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| UniProt ID | ||||||
| EC Number |
EC 6.2.1.45
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| Sequence |
MSSSPLSKKRRVSGPDPKPGSNCSPAQSVLSEVPSVPTNGMAKNGSEADIDEGLYSRQLY
VLGHEAMKRLQTSSVLVSGLRGLGVEIAKNIILGGVKAVTLHDQGTAQWADLSSQFYLRE EDIGKNRAEVSQPRLAELNSYVPVTAYTGPLVEDFLSGFQVVVLTNTPLEDQLRVGEFCH NRGIKLVVADTRGLFGQLFCDFGEEMILTDSNGEQPLSAMVSMVTKDNPGVVTCLDEARH GFESGDFVSFSEVQGMVELNGNQPMEIKVLGPYTFSICDTSNFSDYIRGGIVSQVKVPKK ISFKSLVASLAEPDFVVTDFAKFSRPAQLHIGFQALHQFCAQHGRPPRPRNEEDAAELVA LAQAVNARALPAVQQNNLDEDLIRKLAYVAAGDLAPINAFIGGLAAQEVMKACSGKFMPI MQWLYFDALECLPEDKEVLTEDKCLQRQNRYDGQVAVFGSDLQEKLGKQKYFLVGAGAIG CELLKNFAMIGLGCGEGGEIIVTDMDTIEKSNLNRQFLFRPWDVTKLKSDTAAAAVRQMN PHIRVTSHQNRVGPDTERIYDDDFFQNLDGVANALDNVDARMYMDRRCVYYRKPLLESGT LGTKGNVQVVIPFLTESYSSSQDPPEKSIPICTLKNFPNAIEHTLQWARDEFEGLFKQPA ENVNQYLTDPKFVERTLRLAGTQPLEVLEAVQRSLVLQRPQTWADCVTWACHHWHTQYSN NIRQLLHNFPPDQLTSSGAPFWSGPKRCPHPLTFDVNNPLHLDYVMAAANLFAQTYGLTG SQDRAAVATFLQSVQVPEFTPKSGVKIHVSDQELQSANASVDDSRLEELKATLPSPDKLP GFKMYPIDFEKDDDSNFHMDFIVAASNLRAENYDIPSADRHKSKLIAGKIIPAIATTTAA VVGLVCLELYKVVQGHRQLDSYKNGFLNLALPFFGFSEPLAAPRHQYYNQEWTLWDRFEV QGLQPNGEEMTLKQFLDYFKTEHKLEITMLSQGVSMLYSFFMPAAKLKERLDQPMTEIVS RVSKRKLGRHVRALVLELCCNDESGEDVEVPYVRYTIR 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: Pyrophosphate 2- | Ligand Info | |||||
| Structure Description | Crystal structure of human ubiquitin activating enzyme E1 (Uba1) in complex with ubiquitin | PDB:6DC6 | ||||
| Method | X-ray diffraction | Resolution | 3.14 Å | Mutation | Yes | [4] |
| PDB Sequence |
DIDEGLYSRQ
58 LYVLGHEAMK68 RLQTSSVLVS78 GLRGLGVEIA88 KNIILGGVKA98 VTLHDQGTAQ 108 WADLSSQFYL118 REEDIGKNRA128 EVSQPRLAEL138 NSYVPVTAYT148 GPLVEDFLSG 158 FQVVVLTNTP168 LEDQLRVGEF178 CHNRGIKLVV188 ADTRGLFGQL198 FCDFGEEMIL 208 TDSNGEQPLS218 AMVSMVTKDN228 PGVVTCLDEA238 RHGFESGDFV248 SFSEVQGMVE 258 LNGNQPMEIK268 VLGPYTFSIC278 DTSNFSDYIR288 GGIVSQVKVP298 KKISFKSLVA 308 SLAEPDFVVT318 DFAKFSRPAQ328 LHIGFQALHQ338 FCAQHGRPPR348 PRNEEDAAEL 358 VALAQAVNAR368 ALPAVQQNNL378 DEDLIRKLAY388 VAAGDLAPIN398 AFIGGLAAQE 408 VMKACSGKFM418 PIMQWLYFDA428 LECLPEDKEV438 LTEDKCLQRQ448 NRYDGQVAVF 458 GSDLQEKLGK468 QKYFLVGAGA478 IGCELLKNFA488 MIGLGCGEGG498 EIIVTDMDTI 508 EKSNLNRQFL518 FRPWDVTKLK528 SDTAAAAVRQ538 MNPHIRVTSH548 QNRVGPDTER 558 IYDDDFFQNL568 DGVANALDNV578 DARMYMDRRC588 VYYRKPLLES598 GTLGTKGNVQ 608 VVIPFLTESY618 SSSQDPPEKS628 IPIATLKNFP638 NAIEHTLQWA648 RDEFEGLFKQ 658 PAENVNQYLT668 DPKFVERTLR678 LAGTQPLEVL688 EAVQRSLVLQ698 RPQTWADCVT 708 WACHHWHTQY718 SNNIRQLLHN728 FPPDQLTSSG738 APFWSGPKRC748 PHPLTFDVNN 758 PLHLDYVMAA768 ANLFAQTYGL778 TGSQDRAAVA788 TFLQSVQVPE798 FTPKSVDDSR 825 LEELKATLPS835 PDKLPGFKMY845 PIDFEKDDDS855 NFHMDFIVAA865 SNLRAENYDI 875 PSADRHKSKL885 IAGKIIPAIA895 TTTAAVVGLV905 CLELYKVVQG915 HRQLDSYKNG 925 FLNLALPFFG935 FSEPLAAPRH945 QYYNQEWTLW955 DRFEVQGLQP965 NGEEMTLKQF 975 LDYFKTEHKL985 EITMLSQGVS995 MLYSFFMPAA1005 KLKERLDQPM1015 TEIVSRVSKR 1025 KLGRHVRALV1035 LELCCNDESG1045 EDVEVPYVRY1055 TI
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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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| Ubiquitin mediated proteolysis | hsa04120 | Affiliated Target |
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| Class: Genetic Information Processing => Folding, sorting and degradation | Pathway Hierarchy | ||
| Degree | 35 | Degree centrality | 3.76E-03 | Betweenness centrality | 9.08E-04 |
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| Closeness centrality | 2.27E-01 | Radiality | 1.40E+01 | Clustering coefficient | 1.53E-01 |
| Neighborhood connectivity | 3.28E+01 | Topological coefficient | 6.73E-02 | 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 | ||
| References | Top | |||||
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| REF 1 | Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes. Nat Commun. 2017 Jan 30;8:14286. | |||||
| REF 2 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme. US10202389. | |||||
| REF 3 | The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood. 2010 Mar 18;115(11):2251-9. | |||||
| REF 4 | Crystal structure of a human ubiquitin E1-ubiquitin complex reveals conserved functional elements essential for activity. J Biol Chem. 2018 Nov 23;293(47):18337-18352. | |||||
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