Target Information
| Target General Information | Top | |||||
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| Target ID |
T67416
(Former ID: TTDI01994)
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| Target Name |
Bifunctional aminoacyl-tRNA synthetase (EPRS)
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| Synonyms |
QPRS; QARS; ProlinetRNA ligase; PIG32; GlutamatylprolyltRNA synthetase; Glutamatyl-prolyl-tRNA synthetase; GluRS; EPRS; Cell proliferationinducing gene 32 protein; Cell proliferation-inducing gene 32 protein; Bifunctional glutamate/prolinetRNA ligase; Bifunctional glutamate/proline--tRNA ligase; Bifunctional aminoacyltRNA synthetase
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| Gene Name |
EPRS
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Muscular dystrophy [ICD-11: 8C70] | |||||
| Function |
The phosphorylation of EPRS, induced by interferon-gamma, dissociates the protein from the aminoacyl-tRNA synthetase multienzyme complex and recruits it to the GAIT complex that binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin), suppressing their translation. Interferon-gamma can therefore redirect, in specific cells, the EPRS function from protein synthesis to translation inhibition. Also functions as an effector of the mTORC1 signaling pathway by promoting, through SLC27A1, the uptake of long-chain fatty acid by adipocytes. Thereby, it also plays a role in fat metabolism and more indirectly influences lifespan. Multifunctional protein which is primarily part of the aminoacyl-tRNA synthetase multienzyme complex, also know as multisynthetase complex, that catalyzes the attachment of the cognate amino acid to the corresponding tRNA in a two-step reaction: the amino acid is first activated by ATP to form a covalent intermediate with AMP and is then transferred to the acceptor end of the cognate tRNA.
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| BioChemical Class |
Carbon-oxygen ligase
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| UniProt ID | ||||||
| Sequence |
MATLSLTVNSGDPPLGALLAVEHVKDDVSISVEEGKENILHVSENVIFTDVNSILRYLAR
VATTAGLYGSNLMEHTEIDHWLEFSATKLSSCDSFTSTINELNHCLSLRTYLVGNSLSLA DLCVWATLKGNAAWQEQLKQKKAPVHVKRWFGFLEAQQAFQSVGTKWDVSTTKARVAPEK KQDVGKFVELPGAEMGKVTVRFPPEASGYLHIGHAKAALLNQHYQVNFKGKLIMRFDDTN PEKEKEDFEKVILEDVAMLHIKPDQFTYTSDHFETIMKYAEKLIQEGKAYVDDTPAEQMK AEREQRIDSKHRKNPIEKNLQMWEEMKKGSQFGQSCCLRAKIDMSSNNGCMRDPTLYRCK IQPHPRTGNKYNVYPTYDFACPIVDSIEGVTHALRTTEYHDRDEQFYWIIEALGIRKPYI WEYSRLNLNNTVLSKRKLTWFVNEGLVDGWDDPRFPTVRGVLRRGMTVEGLKQFIAAQGS SRSVVNMEWDKIWAFNKKVIDPVAPRYVALLKKEVIPVNVPEAQEEMKEVAKHPKNPEVG LKPVWYSPKVFIEGADAETFSEGEMVTFINWGNLNITKIHKNADGKIISLDAKLNLENKD YKKTTKVTWLAETTHALPIPVICVTYEHLITKPVLGKDEDFKQYVNKNSKHEELMLGDPC LKDLKKGDIIQLQRRGFFICDQPYEPVSPYSCKEAPCVLIYIPDGHTKEMPTSGSKEKTK VEATKNETSAPFKERPTPSLNNNCTTSEDSLVLYNRVAVQGDVVRELKAKKAPKEDVDAA VKQLLSLKAEYKEKTGQEYKPGNPPAEIGQNISSNSSASILESKSLYDEVAAQGEVVRKL KAEKSPKAKINEAVECLLSLKAQYKEKTGKEYIPGQPPLSQSSDSSPTRNSEPAGLETPE AKVLFDKVASQGEVVRKLKTEKAPKDQVDIAVQELLQLKAQYKSLIGVEYKPVSATGAED KDKKKKEKENKSEKQNKPQKQNDGQRKDPSKNQGGGLSSSGAGEGQGPKKQTRLGLEAKK EENLADWYSQVITKSEMIEYHDISGCYILRPWAYAIWEAIKDFFDAEIKKLGVENCYFPM FVSQSALEKEKTHVADFAPEVAWVTRSGKTELAEPIAIRPTSETVMYPAYAKWVQSHRDL PIKLNQWCNVVRWEFKHPQPFLRTREFLWQEGHSAFATMEEAAEEVLQILDLYAQVYEEL LAIPVVKGRKTEKEKFAGGDYTTTIEAFISASGRAIQGGTSHHLGQNFSKMFEIVFEDPK IPGEKQFAYQNSWGLTTRTIGVMTMVHGDNMGLVLPPRVACVQVVIIPCGITNALSEEDK EALIAKCNDYRRRLLSVNIRVRADLRDNYSPGWKFNHWELKGVPIRLEVGPRDMKSCQFV AVRRDTGEKLTVAENEAETKLQAILEDIQVTLFTRASEDLKTHMVVANTMEDFQKILDSG KIVQIPFCGEIDCEDWIKKTTARDQDLEPGAPSMGAKSLCIPFKPLCELQPGAKCVCGKN PAKYYTLFGRSY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | HT-100 | Drug Info | Phase 2 | Duchenne dystrophy | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | HT-100 | Drug Info | [1] | |||
| 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 | Ligand Info | |||||
| Structure Description | Crystal structure of human prolyl-tRNA synthetase (substrate bound form) | PDB:4K87 | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [3] |
| PDB Sequence |
LEAKKEENLA
25 DWYSQVITKS35 EMIEYHDISG45 CYILRPWAYA55 IWEAIKDFFD65 AEIKKLGVEN 75 CYFPMFVSQS85 ALEKEKTHVA95 DFAPEVAWVT105 RSGKTELAEP115 IAIRPTSETV 125 MYPAYAKWVQ135 SHRDLPIKLN145 QWCNVVRWEF155 KHPQPFLRTR165 EFLWQEGHSA 175 FATMEEAAEE185 VLQILDLYAQ195 VYEELLAIPV205 VKGRKTEKEK215 FAGGDYTTTI 225 EAFISASGRA235 IQGGTSHHLG245 QNFSKMFEIV255 FEDPKIPGEK265 QFAYQNSWGL 275 TTRTIGVMTM285 VHGDNMGLVL295 PPRVACVQVV305 IIPCGITNAL315 SEEDKEALIA 325 KCNDYRRRLL335 SVNIRVRADL345 RDNYSPGWKF355 NHWELKGVPI365 RLEVGPRDMK 375 SCQFVAVRRD385 TGEKLTVAEN395 EAETKLQAIL405 EDIQVTLFTR415 ASEDLKTHMV 425 VANTMEDFQK435 ILDSGKIVQI445 PFCGEIDCED455 WIKKTTARDQ465 SMGAKSLCIP 482 FKPLCELQPG492 AKCVCGKNPA502 KYYTLFGRSY512
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| Ligand Name: AMP-PNP | Ligand Info | |||||
| Structure Description | Crystal structure of human prolyl-tRNA synthetase in complex with halofuginone and ATP analogue | PDB:4HVC | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [4] |
| PDB Sequence |
LEAKKEENLA
1025 DWYSQVITKS1035 EMIEYHDISG1045 CYILRPWAYA1055 IWEAIKDFFD1065 AEIKKLGVEN 1075 CYFPMFVSQS1085 ALEKEKTHVA1095 DFAPEVAWVT1105 RSGKTELAEP1115 IAIRPTSETV 1125 MYPAYAKWVQ1135 SHRDLPIKLN1145 QWCNVVRWEF1155 KHPQPFLRTR1165 EFLWQEGHSA 1175 FATMEEAAEE1185 VLQILDLYAQ1195 VYEELLAIPV1205 VKGRKTEKEK1215 FAGGDYTTTI 1225 EAFISASGRA1235 IQGGTSHHLG1245 QNFSKMFEIV1255 FEDPKIPGEK1265 QFAYQNSWGL 1275 TTRTIGVMTM1285 VHGDNMGLVL1295 PPRVACVQVV1305 IIPCGILSEE1318 DKEALIAKCN 1328 DYRRRLLSVN1338 IRVRADLRDN1348 YSPGWKFNHW1358 ELKGVPIRLE1368 VGPRDMKSCQ 1378 FVAVRRDTGE1388 KLTVAENEAE1398 TKLQAILEDI1408 QVTLFTRASE1418 DLKTHMVVAN 1428 TMEDFQKILD1438 SGKIVQIPFC1448 GEIDCEDWIK1458 KTTARMGAKS1478 LCIPFKPLCE 1488 LQPGAKCVCN1500 PAKYYTLFGR1510 SY
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PHE1097
4.992
ARG1152
2.692
GLU1154
2.829
LYS1156
4.052
PHE1161
3.523
LEU1162
3.808
ARG1163
2.619
THR1164
2.888
PHE1167
3.371
TRP1169
3.765
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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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| Porphyrin metabolism | hsa00860 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Aminoacyl-tRNA biosynthesis | hsa00970 | Affiliated Target |
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| Class: Genetic Information Processing => Translation | Pathway Hierarchy | ||
| Degree | 36 | Degree centrality | 3.87E-03 | Betweenness centrality | 4.67E-03 |
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| Closeness centrality | 2.16E-01 | Radiality | 1.38E+01 | Clustering coefficient | 1.68E-01 |
| Neighborhood connectivity | 1.21E+01 | Topological coefficient | 6.02E-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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| 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 | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| BioCyc | [+] 1 BioCyc Pathways | + | ||||
| 1 | TRNA charging | |||||
| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Porphyrin and chlorophyll metabolism | |||||
| 2 | Aminoacyl-tRNA biosynthesis | |||||
| 3 | Metabolic pathways | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Heme biosynthesis | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Arginine and Proline Metabolism | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Parkinsons Disease Pathway | |||||
| 2 | tRNA Aminoacylation | |||||
| References | Top | |||||
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| REF 1 | Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol. 2012 Feb 12;8(3):311-7. | |||||
| REF 2 | ClinicalTrials.gov (NCT02525302) HT-100 Long-term Study in DMD Patients Who Completed HALO-DMD-02. | |||||
| REF 3 | Conformational changes in human prolyl-tRNA synthetase upon binding of the substrates proline and ATP and the inhibitor halofuginone. Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):2136-45. | |||||
| REF 4 | ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature. 2013 Feb 7;494(7435):121-4. | |||||
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