Target Information
| Target General Information | Top | |||||
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| Target ID |
T85733
(Former ID: TTDR01192)
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| Target Name |
DNA topoisomerase II beta (TOP2B)
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| Synonyms |
Topo IIbeta; TOP2beta; TOP2B
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| Gene Name |
TOP2B
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| 2 | Chemoprotection [ICD-11: N.A.] | |||||
| Function |
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks.
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| BioChemical Class |
ATP-hydrolyzing DNA topoisomerase
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| UniProt ID | ||||||
| EC Number |
EC 5.6.2.3
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| Sequence |
MAKSGGCGAGAGVGGGNGALTWVTLFDQNNAAKKEESETANKNDSSKKLSVERVYQKKTQ
LEHILLRPDTYIGSVEPLTQFMWVYDEDVGMNCREVTFVPGLYKIFDEILVNAADNKQRD KNMTCIKVSIDPESNIISIWNNGKGIPVVEHKVEKVYVPALIFGQLLTSSNYDDDEKKVT GGRNGYGAKLCNIFSTKFTVETACKEYKHSFKQTWMNNMMKTSEAKIKHFDGEDYTCITF QPDLSKFKMEKLDKDIVALMTRRAYDLAGSCRGVKVMFNGKKLPVNGFRSYVDLYVKDKL DETGVALKVIHELANERWDVCLTLSEKGFQQISFVNSIATTKGGRHVDYVVDQVVGKLIE VVKKKNKAGVSVKPFQVKNHIWVFINCLIENPTFDSQTKENMTLQPKSFGSKCQLSEKFF KAASNCGIVESILNWVKFKAQTQLNKKCSSVKYSKIKGIPKLDDANDAGGKHSLECTLIL TEGDSAKSLAVSGLGVIGRDRYGVFPLRGKILNVREASHKQIMENAEINNIIKIVGLQYK KSYDDAESLKTLRYGKIMIMTDQDQDGSHIKGLLINFIHHNWPSLLKHGFLEEFITPIVK ASKNKQELSFYSIPEFDEWKKHIENQKAWKIKYYKGLGTSTAKEAKEYFADMERHRILFR YAGPEDDAAITLAFSKKKIDDRKEWLTNFMEDRRQRRLHGLPEQFLYGTATKHLTYNDFI NKELILFSNSDNERSIPSLVDGFKPGQRKVLFTCFKRNDKREVKVAQLAGSVAEMSAYHH GEQALMMTIVNLAQNFVGSNNINLLQPIGQFGTRLHGGKDAASPRYIFTMLSTLARLLFP AVDDNLLKFLYDDNQRVEPEWYIPIIPMVLINGAEGIGTGWACKLPNYDAREIVNNVRRM LDGLDPHPMLPNYKNFKGTIQELGQNQYAVSGEIFVVDRNTVEITELPVRTWTQVYKEQV LEPMLNGTDKTPALISDYKEYHTDTTVKFVVKMTEEKLAQAEAAGLHKVFKLQTTLTCNS MVLFDHMGCLKKYETVQDILKEFFDLRLSYYGLRKEWLVGMLGAESTKLNNQARFILEKI QGKITIENRSKKDLIQMLVQRGYESDPVKAWKEAQEKAAEEDETQNQHDDSSSDSGTPSG PDFNYILNMSLWSLTKEKVEELIKQRDAKGREVNDLKRKSPSDLWKEDLAAFVEELDKVE SQEREDVLAGMSGKAIKGKVGKPKVKKLQLEETMPSPYGRRIIPEITAMKADASKKLLKK KKGDLDTAAVKVEFDEEFSGAPVEGAGEEALTPSVPINKGPKPKREKKEPGTRVRKTPTS SGKPSAKKVKKRNPWSDDESKSESDLEETEPVVIPRDSLLRRAAAERPKYTFDFSEEEDD DADDDDDDNNDLEELKVKASPITNDGEDEFVPSDGLDKDEYTFSPGKSKATPEKSLHDKK SQDFGNLFSFPSYSQKSEDDSAKFDSNEEDSASVFSPSFGLKQTDKVPSKTVAAKKGKPS SDTVPKPKRAPKQKKVVEAVNSDSDSEFGIPKKTTTPKGKGRGAKKRKASGSENEGDYNP GRKTSKTTSKKPKKTSFDQDSDVDIFPSDFPTEPPSLPRTGRARKEVKYFAESDEEEDDV DFAMFN 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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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Dexrazoxane | Drug Info | Approved | Breast cancer | [2], [3] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | XB-947 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
| 2 | XK-469 | Drug Info | Phase 1 | Solid tumour/cancer | [5] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | Dexrazoxane | Drug Info | [1] | |||
| 2 | A-62176 | Drug Info | [8] | |||
| 3 | 3'-THIO-THYMIDINE-5'-PHOSPHATE | Drug Info | [9] | |||
| 4 | AMP-PNP | Drug Info | [9] | |||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | XB-947 | Drug Info | [6] | |||
| 2 | XK-469 | Drug Info | [7] | |||
| 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: Etoposide | Ligand Info | |||||
| Structure Description | Human topoisomerase IIbeta in complex with DNA and etoposide | PDB:3QX3 | ||||
| Method | X-ray diffraction | Resolution | 2.16 Å | Mutation | No | [10] |
| PDB Sequence |
KGIPKLDDAN
461 DAGGKHSLEC471 TLILTEGDSA481 KSLAVSGLGV491 IGRDRYGVFP501 LRGKILNVRE 511 ASHKQIMENA521 EINNIIKIVG531 LQYKKSYDDA541 ESLKTLRYGK551 IMIMTDQDQD 561 GSHIKGLLIN571 FIHHNWPSLL581 KHGFLEEFIT591 KEAKEYFADM647 ERHRILFRYA 657 GPEDDAAITL667 AFSKKKIDDR677 KEWLTNFMED687 RRQRRLHGLK707 HLTYNDFINK 717 ELILFSNSDN727 ERSIPSLVDG737 FKPGQRKVLF747 TCFKRNDKRE757 VKVAQLAGSV 767 AEMSAYHHGE777 QALMMTIVNL787 AQNFVGSNNI797 NLLQPIGQFG807 TRLHGGKDAA 817 SPRYIFTMLS827 TLARLLFPAV837 DDNLLKFLYD847 DNQRVEPEWY857 IPIIPMVLIN 867 GAEGIGTGWA877 CKLPNYDARE887 IVNNVRRMLD897 GLDPHPMLPN907 YKNFKGTIQE 917 LGQNQYAVSG927 EIFVVDRNTV937 EITELPVRTW947 TQVYKEQVLE957 PMLNGTDKTP 967 ALISDYKEYH977 TDTTVKFVVK987 MTEEKLAQAE997 AAGLHKVFKL1007 QTTLTCNSMV 1017 LFDHMGCLKK1027 YETVQDILKE1037 FFDLRLSYYG1047 LRKEWLVGML1057 GAESTKLNNQ 1067 ARFILEKIQG1077 KITIENRSKK1087 DLIQMLVQRG1097 YESDPVKAWK1107 EAQEGPDFNY 1140 ILNMSLWSLT1150 KEKVEELIKQ1160 RDAKGREVND1170 LKRKSPSDLW1180 KEDLAAFVEE 1190 LDKVESQERE1200 D
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| Ligand Name: Mitoxantrone | Ligand Info | |||||
| Structure Description | Human topoisomerase iibeta in complex with DNA and mitoxantrone | PDB:4G0V | ||||
| Method | X-ray diffraction | Resolution | 2.55 Å | Mutation | No | [11] |
| PDB Sequence |
KGIPKLDDAN
461 DAGGKHSLEC471 TLILTEGDSA481 KSLAVSGLGV491 IGRDRYGVFP501 LRGKILNVRE 511 ASHKQIMENA521 EINNIIKIVG531 LQYKKSYDDA541 ESLKTLRYGK551 IMIMTDQDQD 561 GSHIKGLLIN571 FIHHNWPSLL581 KHGFLEEFIT591 DMERHRILFR655 YAGPEDDAAI 665 TLAFSKKKID675 DRKEWLTNFM685 EDRRQRRLHG695 LKHLTYNDFI715 NKELILFSNS 725 DNERSIPSLV735 DGFKPGQRKV745 LFTCFKRNDK755 REVKVAQLAG765 SVAEMSAYHH 775 GEQALMMTIV785 NLAQNFVGSN795 NINLLQPIGQ805 FGTRLHGGKD815 AASPRYIFTM 825 LSTLARLLFP835 AVDDNLLKFL845 YDDNQRVEPE855 WYIPIIPMVL865 INGAEGIGTG 875 WACKLPNYDA885 REIVNNVRRM895 LDGLDPHPML905 PNYKNFKGTI915 QELGQNQYAV 925 SGEIFVVDRN935 TVEITELPVR945 TWTQVYKEQV955 LEPMLNGTDK965 TPALISDYKE 975 YHTDTTVKFV985 VKMTEEKLAQ995 AEAAGLHKVF1005 KLQTTLTCNS1015 MVLFDHMGCL 1025 KKYETVQDIL1035 KEFFDLRLSY1045 YGLRKEWLVG1055 MLGAESTKLN1065 NQARFILEKI 1075 QGKITIENRS1085 KKDLIQMLVQ1095 RGYESDPVKA1105 WKEAQEGPDF1138 NYILNMSLWS 1148 LTKEKVEELI1158 KQRDAKGREV1168 NDLKRKSPSD1178 LWKEDLAAFV1188 EELDKVESQE 1198 RED
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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 | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 2.12E-05 |
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| Closeness centrality | 2.15E-01 | Radiality | 1.38E+01 | Clustering coefficient | 5.00E-01 |
| Neighborhood connectivity | 3.20E+01 | Topological coefficient | 2.11E-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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| 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 | ||
| 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 Affiliated Biological Pathways | Top | |||||
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| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | DNA replication | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7330). | |||||
| REF 3 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076068. | |||||
| REF 4 | A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours. Eur J Cancer. 2008 August; 44(12): 1684-1692. | |||||
| REF 5 | ClinicalTrials.gov (NCT00028522) R(+)XK469 in Treating Patients With Advanced Neuroblastoma. U.S. National Institutes of Health. | |||||
| REF 6 | XK469, a selective topoisomerase IIbeta poison. Proc Natl Acad Sci U S A. 1999 October 12; 96(21): 12168-12173. | |||||
| REF 7 | A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.Pharmacogenet Genomics.2014 Feb;24(2):129-32. | |||||
| REF 8 | Design of new topoisomerase II inhibitors based upon a quinobenzoxazine self-assembly model. J Med Chem. 1998 Oct 22;41(22):4273-8. | |||||
| REF 9 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 10 | Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science. 2011 Jul 22;333(6041):459-62. | |||||
| REF 11 | On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res. 2013 Dec;41(22):10630-40. | |||||
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