Target Information
| Target General Information | Top | |||||
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| Target ID |
T47583
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| Target Name |
Werner syndrome ATP-dependent helicase (WRN)
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| Synonyms |
DNA helicase, RecQ-like type 3; RecQ3; Exonuclease WRN; RecQ protein-like 2
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| Gene Name |
WRN
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Mature T-cell lymphoma [ICD-11: 2A90] | |||||
| Function |
Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation.
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| UniProt ID | ||||||
| EC Number |
EC 3.1.-.-
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| Sequence |
MSEKKLETTAQQRKCPEWMNVQNKRCAVEERKACVRKSVFEDDLPFLEFTGSIVYSYDAS
DCSFLSEDISMSLSDGDVVGFDMEWPPLYNRGKLGKVALIQLCVSESKCYLFHVSSMSVF PQGLKMLLENKAVKKAGVGIEGDQWKLLRDFDIKLKNFVELTDVANKKLKCTETWSLNSL VKHLLGKQLLKDKSIRCSNWSKFPLTEDQKLYAATDAYAGFIIYRNLEILDDTVQRFAIN KEEEILLSDMNKQLTSISEEVMDLAKHLPHAFSKLENPRRVSILLKDISENLYSLRRMII GSTNIETELRPSNNLNLLSFEDSTTGGVQQKQIREHEVLIHVEDETWDPTLDHLAKHDGE DVLGNKVERKEDGFEDGVEDNKLKENMERACLMSLDITEHELQILEQQSQEEYLSDIAYK STEHLSPNDNENDTSYVIESDEDLEMEMLKHLSPNDNENDTSYVIESDEDLEMEMLKSLE NLNSGTVEPTHSKCLKMERNLGLPTKEEEEDDENEANEGEEDDDKDFLWPAPNEEQVTCL KMYFGHSSFKPVQWKVIHSVLEERRDNVAVMATGYGKSLCFQYPPVYVGKIGLVISPLIS LMEDQVLQLKMSNIPACFLGSAQSENVLTDIKLGKYRIVYVTPEYCSGNMGLLQQLEADI GITLIAVDEAHCISEWGHDFRDSFRKLGSLKTALPMVPIVALTATASSSIREDIVRCLNL RNPQITCTGFDRPNLYLEVRRKTGNILQDLQPFLVKTSSHWEFEGPTIIYCPSRKMTQQV TGELRKLNLSCGTYHAGMSFSTRKDIHHRFVRDEIQCVIATIAFGMGINKADIRQVIHYG APKDMESYYQEIGRAGRDGLQSSCHVLWAPADINLNRHLLTEIRNEKFRLYKLKMMAKME KYLHSSRCRRQIILSHFEDKQVQKASLGIMGTEKCCDNCRSRLDHCYSMDDSEDTSWDFG PQAFKLLSAVDILGEKFGIGLPILFLRGSNSQRLADQYRRHSLFGTGKDQTESWWKAFSR QLITEGFLVEVSRYNKFMKICALTKKGRNWLHKANTESQSLILQANEELCPKKLLLPSSK TVSSGTKEHCYNQVPVELSTEKKSNLEKLYSYKPCDKISSGSNISKKSIMVQSPEKAYSS SQPVISAQEQETQIVLYGKLVEARQKHANKMDVPPAILATNKILVDMAKMRPTTVENVKR IDGVSEGKAAMLAPLLEVIKHFCQTNSVQTDLFSSTKPQEEQKTSLVAKNKICTLSQSMA ITYSLFQEKKMPLKSIAESRILPLMTIGMHLSQAVKAGCPLDLERAGLTPEVQKIIADVI RNPPVNSDMSKISLIRMLVPENIDTYLIHMAIEILKHGPDSGLQPSCDVNKRRCFPGSEE ICSSSKRSKEEVGINTETSSAERKRRLPVWFAKGSDTSKKLMDKTKRGGLFS 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: adenosine diphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of Werner syndrome helicase | PDB:6YHR | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [2] |
| PDB Sequence |
LWPAPNEEQV
537 TCLKMYFGHS547 SFKPVQWKVI557 HSVLEERRDN567 VAVMATGYGK577 SLCFQYPPVY 587 VGKIGLVISP597 LISLMEDQVL607 QLKMSNIPAC617 FLGSAQSENV627 LTDIKLGKYR 637 IVYVTPEYCS647 GNMGLLQQLE657 ADIGITLIAV667 DEAHCISEWG677 HDFRDSFRKL 687 GSLKTALPMV697 PIVALTATAS707 SSIREDIVRC717 LNLRNPQITC727 TGFDRPNLYL 737 EVRRKTGNIL747 QDLQPFLVKT757 SSHWEFEGPT767 IIYCPSRKMT777 QQVTGELRKL 787 NLSCGTYHAG797 MSFSTRKDIH807 HRFVRDEIQC817 VIATIAFGMG827 INKADIRQVI 837 HYGAPKDMES847 YYQEIGRAGR857 DGLQSSCHVL867 WAPADINLNR877 HLLTEIRNEK 887 FRLYKLKMMA897 KMEKYLHSSR907 CRRQIILSHF917 EDKQVQKASL927 GIMGTEKCCD 937 NCRSRLDHCY947 SMDTSWDFGP961 QAFKLLSAVD971 ILGEKFGIGL981 PILFLRGSNS 991 QRLADQYRRH1001 SLFGTGKDQT1011 ESWWKAFSRQ1021 LITEGFLVEV1031 SRYNKFMKIC 1041 ALTKKGRNWL1051 HKANTESQSL1061 ILQANEELCP1071 K
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| Ligand Name: 2'-Deoxyguanosine-5'-Monophosphate | Ligand Info | |||||
| Structure Description | WRN exonuclease, Mn dGMP complex | PDB:2FC0 | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
| PDB Sequence |
HHSVFEDDLP
45 FLEFTGSIVY55 SYDASDCSFL65 SEDISMSLSD75 GDVVGFDMEW85 PPLYNRGKLG 95 KVALIQLCVS105 ESKCYLFHVS115 SMSVFPQGLK125 MLLENKAVKK135 AGVGIEGDQW 145 KLLRDFDIKL155 KNFVELTDVA165 NKKLKCTETW175 SLNSLVKHLL185 GKQLLKDKSI 195 RCSNWSKFPL205 TEDQKLYAAT215 DAYAGFIIYR225 NLEILD
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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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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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| Degree | 43 | Degree centrality | 4.62E-03 | Betweenness centrality | 1.26E-03 |
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| Closeness centrality | 2.39E-01 | Radiality | 1.42E+01 | Clustering coefficient | 2.35E-01 |
| Neighborhood connectivity | 3.85E+01 | Topological coefficient | 6.74E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells. J Hematol Oncol. 2016 Nov 9;9(1):121. | |||||
| REF 2 | Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers. Life Sci Alliance. 2020 Nov 16;4(1):e202000795. | |||||
| REF 3 | WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nat Struct Mol Biol. 2006 May;13(5):414-22. | |||||
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