Target Information
Target General Information | Top | |||||
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Target ID |
T96311
(Former ID: TTDC00245)
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Target Name |
NEDD8-activating enzyme E1C (UBA3)
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Synonyms |
Ubiquitin-like modifier-activating enzyme 3; Ubiquitin-activating enzyme E1C; Ubiquitin-activating enzyme 3; UBE1C; NEDD8-activating enzyme E1 catalytic subunit
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Gene Name |
UBA3
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Target Type |
Literature-reported target
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[1] | ||||
Function |
E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Down-regulates steroid receptor activity. Necessary for cell cycle progression. Catalytic subunit of the dimeric UBA3-NAE1 E1 enzyme.
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BioChemical Class |
Carbon-sulfur ligase
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UniProt ID | ||||||
EC Number |
EC 6.2.1.-
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Sequence |
MADGEEPEKKRRRIEELLAEKMAVDGGCGDTGDWEGRWNHVKKFLERSGPFTHPDFEPST
ESLQFLLDTCKVLVIGAGGLGCELLKNLALSGFRQIHVIDMDTIDVSNLNRQFLFRPKDI GRPKAEVAAEFLNDRVPNCNVVPHFNKIQDFNDTFYRQFHIIVCGLDSIIARRWINGMLI SLLNYEDGVLDPSSIVPLIDGGTEGFKGNARVILPGMTACIECTLELYPPQVNFPMCTIA SMPRLPEHCIEYVRMLQWPKEQPFGEGVPLDGDDPEHIQWIFQKSLERASQYNIRGVTYR LTQGVVKRIIPAVASTNAVIAAVCATEVFKIATSAYIPLNNYLVFNDVDGLYTYTFEAER KENCPACSQLPQNIQFSPSAKLQEVLDYLTNSASLQMKSPAITATLEGKNRTLYLQSVTS IEERTRPNLSKTLKELGLVDGQELAVADVTTPQTVLFKLHFTS 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: Adenosine triphosphate | Ligand Info | |||||
Structure Description | Structure of APPBP1-UBA3~NEDD8-NEDD8-MgATP-Ubc12(C111A), a trapped ubiquitin-like protein activation complex | PDB:2NVU | ||||
Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [2] |
PDB Sequence |
KIEEGKLVIW
1011 INGDKGYNGL1021 AEVGKKFEKD1031 TGIKVTVEHP1041 DKLEEKFPQV1051 AATGDGPDII 1061 FWAHDRFGGY1071 AQSGLLAEIT1081 PDKAFQDKLY1091 PFTWDAVRYN1101 GKLIAYPIAV 1111 EALSLIYNKD1121 LLPNPPKTWE1131 EIPALDKELK1141 AKGKSALMFN1151 LQEPYFTWPL 1161 IAADGGYAFK1171 YENGKYDIKD1181 VGVDNAGAKA1191 GLTFLVDLIK1201 NKHMNADTDY 1211 SIAEAAFNKG1221 ETAMTINGPW1231 AWSNIDTSKV1241 NYGVTVLPTF1251 KGQPSKPFVG 1261 VLSAGINAAS1271 PNKELAKEFL1281 ENYLLTDEGL1291 EAVNKDKVAL1305 KSYEEEATME 1323 NAQKGEIMPN1333 IPQMSAFWYA1343 VRTAVINAAS1353 GRQTVDAALA1363 AAQTNAAADW 2013 EGRWNHVKKF2023 LERSGPFTHP2033 DFEPSTESLQ2043 FLLDTCKVLV2053 IGAGGLGCEL 2063 LKNLALSGFR2073 QIHVIDMDTI2083 DVSNLNRQFL2093 FRPKDIGRPK2103 AEVAAEFLND 2113 RVPNCNVVPH2123 FNKIQDFNDT2133 FYRQFHIIVC2143 GLDSIIARRW2153 INGMLISLLN 2163 YEDGVLDPSS2173 IVPLIDGGTE2183 GFKGNARVIL2193 PGMTACIECT2203 LELYPPQVNF 2213 PMCTIASMPR2223 LPEHCIEYVR2233 MLQWPKEQPF2243 GEGVPLDGDD2253 PEHIQWIFQK 2263 SLERASQYNI2273 RGVTYRLTQG2283 VVKRIIPAVA2293 STNAVIAAVC2303 ATEVFKIATS 2313 AYIPLNNYLV2323 FNDVDGLYTY2333 TFEAERKENC2343 PACSQLPQNI2353 QFSPSAKLQE 2363 VLDYLTNSAS2373 LQMKSPAITA2383 TLEGKNRTLY2393 LQSVTSIEER2403 TRPNLSKTLK 2413 ELGLVDGQEL2423 AVADVTTPQT2433 VLFKLHFTS
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GLY2055
4.142
ALA2056
3.078
GLY2057
2.955
GLY2058
4.269
ILE2078
4.538
ASP2079
2.751
MET2080
3.413
ASP2081
3.037
SER2086
4.151
ASN2087
3.259
ARG2090
3.305
GLN2091
3.674
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: MLN4924 | Ligand Info | |||||
Structure Description | Structure of NEDD8-activating enzyme in complex with NEDD8 and MLN4924 | PDB:3GZN | ||||
Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [3] |
PDB Sequence |
DWEGRWNHVK
42 KFLERSGPFT52 HPDFEPSTES62 LQFLLDTCKV72 LVIGAGGLGC82 ELLKNLALSG 92 FRQIHVIDMD102 TIDVSNLNRQ112 FLFRPKDIGR122 PKAEVAAEFL132 NDRVPNCNVV 142 PHFNKIQDFN152 DTFYRQFHII162 VCGLDSIIAR172 RWINGMLISL182 LNYEDGVLDP 192 SSIVPLIDGG202 TEGFKGNARV212 ILPGMTACIE222 CTLELYPPQV232 NFPMCTIASM 242 PRLPEHCIEY252 VRMLQWPKEQ262 PFGEGVPLDG272 DDPEHIQWIF282 QKSLERASQY 292 NIRGVTYRLT302 QGVVKRIIPA312 VASTNAVIAA322 VCATEVFKIA332 TSAYIPLNNY 342 LVFNDVDGLY352 TYTFEAERKE362 NCPACSQLPQ372 NIQFSPSAKL382 QEVLDYLTNS 392 ASLQMKSPAI402 TATLEGKNRT412 LYLQSVTSIE422 ERTRPNLSKL433 KELGLVDGQE 443 LAVADVTTPQ453 TVLFKLHFT
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GLY76
3.873
ALA77
4.399
GLY78
3.259
GLY79
2.662
LEU80
4.521
ILE99
4.286
ASP100
2.703
MET101
3.406
ASP102
3.625
ARG111
3.696
GLN112
3.675
LYS124
3.027
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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 | 14 | Degree centrality | 1.50E-03 | Betweenness centrality | 2.85E-04 |
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Closeness centrality | 2.14E-01 | Radiality | 1.38E+01 | Clustering coefficient | 1.98E-01 |
Neighborhood connectivity | 2.14E+01 | Topological coefficient | 1.36E-01 | Eccentricity | 12 |
Download | Click to Download the Full PPI Network of This Target | ||||
Target Regulators | Top | |||||
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Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Drug Resistance Mutation (DRM) |
Target Affiliated Biological Pathways | Top | |||||
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BioCyc | [+] 1 BioCyc Pathways | + | ||||
1 | Protein ubiquitylation | |||||
KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | Ubiquitin mediated proteolysis | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Ubiquitin proteasome pathway | |||||
PID Pathway | [+] 3 PID Pathways | + | ||||
1 | Coregulation of Androgen receptor activity | |||||
2 | Validated nuclear estrogen receptor beta network | |||||
3 | Validated nuclear estrogen receptor alpha network | |||||
Reactome | [+] 3 Reactome Pathways | + | ||||
1 | Dectin-1 mediated noncanonical NF-kB signaling | |||||
2 | NIK-->noncanonical NF-kB signaling | |||||
3 | Antigen processing: Ubiquitination & Proteasome degradation |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Mutations in UBA3 confer resistance to the NEDD8-activating enzyme inhibitor MLN4924 in human leukemic cells.PLoS One.2014 Apr 1;9(4):e93530. | |||||
REF 2 | Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity. Nature. 2007 Jan 25;445(7126):394-8. | |||||
REF 3 | Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Mol Cell. 2010 Jan 15;37(1):102-11. |
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