Target Information
Target General Information | Top | |||||
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Target ID |
T25200
(Former ID: TTDI02446)
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Target Name |
Ribonuclease L (RNASEL)
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Synonyms |
Ribonuclease 4; RNase L; RNS4; 25Adependent ribonuclease; 25Adependent RNase; 2-5A-dependent ribonuclease; 2-5A-dependent RNase
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Gene Name |
RNASEL
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Target Type |
Literature-reported target
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[1] | ||||
Function |
In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis. Might play a central role in the regulation of mRNA turnover. Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length. Endoribonuclease that functions in the interferon (IFN) antiviral response.
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BioChemical Class |
Endoribonucleases
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UniProt ID | ||||||
EC Number |
EC 3.1.26.-
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Sequence |
MESRDHNNPQEGPTSSSGRRAAVEDNHLLIKAVQNEDVDLVQQLLEGGANVNFQEEEGGW
TPLHNAVQMSREDIVELLLRHGADPVLRKKNGATPFILAAIAGSVKLLKLFLSKGADVNE CDFYGFTAFMEAAVYGKVKALKFLYKRGANVNLRRKTKEDQERLRKGGATALMDAAEKGH VEVLKILLDEMGADVNACDNMGRNALIHALLSSDDSDVEAITHLLLDHGADVNVRGERGK TPLILAVEKKHLGLVQRLLEQEHIEINDTDSDGKTALLLAVELKLKKIAELLCKRGASTD CGDLVMTARRNYDHSLVKVLLSHGAKEDFHPPAEDWKPQSSHWGAALKDLHRIYRPMIGK LKFFIDEKYKIADTSEGGIYLGFYEKQEVAVKTFCEGSPRAQREVSCLQSSRENSHLVTF YGSESHRGHLFVCVTLCEQTLEACLDVHRGEDVENEEDEFARNVLSSIFKAVQELHLSCG YTHQDLQPQNILIDSKKAAHLADFDKSIKWAGDPQEVKRDLEDLGRLVLYVVKKGSISFE DLKAQSNEEVVQLSPDEETKDLIHRLFHPGEHVRDCLSDLLGHPFFWTWESRYRTLRNVG NESDIKTRKSESEILRLLQPGPSEHSKSFDKWTTKINECVMKKMNKFYEKRGNFYQNTVG DLLKFIRNLGEHIDEEKHKKMKLKIGDPSLYFQKTFPDLVIYVYTKLQNTEYRKHFPQTH SPNKPQCDGAGGASGLASPGC Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T95K0S |
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: L-betagamma-meATP | Ligand Info | |||||
Structure Description | Complete human RNase L in complex with 2-5A (5'-ppp heptamer), AMPPCP and RNA substrate. | PDB:4OAV | ||||
Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [2] |
PDB Sequence |
EDNHLLIKAV
33 QNEDVDLVQQ43 LLEGGANVNF53 QEEEGGWTPL63 HNAVQMSRED73 IVELLLRHGA 83 DPVLRKKNGA93 TPFILAAIAG103 SVKLLKLFLS113 KGADVNECDF123 YGFTAFMEAA 133 VYGKVKALKF143 LYKRGANVNL153 RRKTKEDQER163 LRKGGATALM173 DAAEKGHVEV 183 LKILLDEMGA193 DVNACDNMGR203 NALIHALLSS213 DDSDVEAITH223 LLLDHGADVN 233 VRGERGKTPL243 ILAVEKKHLG253 LVQRLLEQEH263 IEINDTDSDG273 KTALLLAVEL 283 KLKKIAELLC293 KRGASTDCGD303 LVMTARRNYD313 HSLVKVLLSH323 GAKEWKPQSS 341 HWGAALKDLH351 RIYRPMIGKL361 KFFIDEKYKI371 ADTSEGGIYL381 GFYEKQEVAV 391 KTFCEGSPRA401 QREVSCLQSS411 RENSHLVTFY421 GSESHRGHLF431 VCVTLCEQTL 441 EACLDVEEDE459 FARNVLSSIF469 KAVQELHLSC479 GYTHQDLQPQ489 NILIDSKKAA 499 HLADFDKSIK509 WAGDPQEVKR519 DLEDLGRLVL529 YVVKKGSISF539 EDLKAQSNEE 549 VVQLSPDEET559 KDLIHRLFHP569 GEHVRDCLSD579 LLGHPFFWTW589 ESRYRTLRNV 599 GNESDIKTRK609 SESEILRLLQ619 PGPSEHSKSF629 DKWTTKINEC639 VMKKMNKFYE 649 KRGNFYQNTV659 GDLLKFIRNL669 GENIDKMKLK684 IGDPSLYFQK694 TFPDLVIYVY 704 TKLQNTEYRK714 HFP
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TRP343
4.567
ILE371
3.629
ALA372
3.303
ASP373
4.865
THR374
2.988
SER375
2.218
ILE379
3.372
ALA390
3.263
LYS392
2.853
ARG400
2.924
GLU404
4.913
VAL418
4.383
VAL434
3.370
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Ligand Name: adenosine diphosphate | Ligand Info | |||||
Structure Description | Complete human RNase L in complex with biological activators. | PDB:4OAU | ||||
Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | Yes | [2] |
PDB Sequence |
DNHLLIKAVQ
34 NEDVDLVQQL44 LEGGANVNFQ54 EEEGGWTPLH64 NAVQMSREDI74 VELLLRHGAD 84 PVLRKKNGAT94 PFILAAIAGS104 VKLLKLFLSK114 GADVNECDFY124 GFTAFMEAAV 134 YGKVKALKFL144 YKRGANVNLR154 RKTKEDQERL164 RKGGATALMD174 AAEKGHVEVL 184 KILLDEMGAD194 VNACDNMGRN204 ALIHALLSSD214 DSDVEAITHL224 LLDHGADVNV 234 RGERGKTPLI244 LAVEKKHLGL254 VQRLLEQEHI264 EINDTDSDGK274 TALLLAVELK 284 LKKIAELLCK294 RGASTDCGDL304 VMTARRNYDH314 SLVKVLLSHG324 AKEDFHPPAE 334 DWKPQSSHWG344 AALKDLHRIY354 RPMIGKLKFF364 IDEKYKIADT374 SEGGIYLGFY 384 EKQEVAVKTF394 CEGSPRAQRE404 VSCLQSSREN414 SHLVTFYGSE424 SHRGHLFVCV 434 TLCEQTLEAC444 LDVHRGEDVE454 NEEDEFARNV464 LSSIFKAVQE474 LHLSCGYTHQ 484 DLQPQNILID494 SKKAAHLADF504 DKSIKWAGDP514 QEVKRDLEDL524 GRLVLYVVKK 534 GSISFEDLKA544 QSNEEVVQLS554 PDEETKDLIH564 RLFHPGEHVR574 DCLSDLLGHP 584 FFWTWESRYR594 TLRNVGNESD604 IKTRKSESEI614 LRLLQPEHSK627 SFDKWTTKIN 637 ECVMKKMNKF647 YEKRGNFYQN657 TVGDLLKFIR667 NLGENIDEEK677 HKKMKLKIGD 687 PSLYFQKTFP697 DLVIYVYTKL707 QNTEYRKHFP717 QT
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TRP343
4.824
ILE371
3.177
ALA372
3.315
ASP373
4.887
THR374
2.298
SER375
4.209
ILE379
3.147
ALA390
3.347
LYS392
2.993
ARG400
4.344
GLU404
4.882
VAL418
4.571
VAL434
3.405
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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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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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NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 19 | Degree centrality | 2.04E-03 | Betweenness centrality | 2.57E-04 |
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Closeness centrality | 2.19E-01 | Radiality | 1.38E+01 | Clustering coefficient | 7.08E-01 |
Neighborhood connectivity | 3.46E+01 | Topological coefficient | 1.85E-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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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 |
References | Top | |||||
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REF 1 | Role of 2-5A-dependent RNase-L in senescence and longevity. Oncogene. 2007 May 10;26(21):3081-8. | |||||
REF 2 | Structure of human RNase L reveals the basis for regulated RNA decay in the IFN response. Science. 2014 Mar 14;343(6176):1244-8. |
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