Target Information
| Target General Information | Top | |||||
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| Target ID |
T06958
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| Target Name |
DNA polymerase beta (POLB)
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| Gene Name |
POLB
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Repair polymerase that plays a key role in base-excision repair. Has 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity that removes the 5' sugar phosphate and also acts as a DNA polymerase that adds one nucleotide to the 3' end of the arising single-nucleotide gap. Conducts 'gap-filling' DNA synthesis in a stepwise distributive fashion rather than in a processive fashion as for other DNA polymerases.
Click to Show/Hide
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| UniProt ID | ||||||
| EC Number |
EC 2.7.7.7
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| Sequence |
MSKRKAPQETLNGGITDMLTELANFEKNVSQAIHKYNAYRKAASVIAKYPHKIKSGAEAK
KLPGVGTKIAEKIDEFLATGKLRKLEKIRQDDTSSSINFLTRVSGIGPSAARKFVDEGIK TLEDLRKNEDKLNHHQRIGLKYFGDFEKRIPREEMLQMQDIVLNEVKKVDSEYIATVCGS FRRGAESSGDMDVLLTHPSFTSESTKQPKLLHQVVEQLQKVHFITDTLSKGETKFMGVCQ LPSKNDEKEYPHRRIDIRLIPKDQYYCGVLYFTGSDIFNKNMRAHALEKGFTINEYTIRP LGVTGVAGEPLPVDSEKDIFDYIQWKYREPKDRSE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A03025 | |||||
| HIT2.0 ID | T23IBY | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | FF-10502 | Drug Info | Phase 1/2 | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | FF-10502 | 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 triphosphate | Ligand Info | |||||
| Structure Description | DNA POLYMERASE BETA (POL B) (E.C.2.7.7.7) COMPLEXED WITH SEVEN BASE PAIRS OF DNA; SOAKED IN THE PRESENCE OF ATP (1 MILLIMOLAR) AND MNCL2 (5 MILLIMOLAR) | PDB:8ICN | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [3] |
| PDB Sequence |
ETLNGGITDM
18 LTELANFEKN28 VSQAIHKYNA38 YRKAASVIAK48 YPHKIKSGAE58 AKKLPGVGTK 68 IAEKIDEFLA78 TGKLRKLEKI88 RQDDTSSSIN98 FLTRVSGIGP108 SAARKFVDEG 118 IKTLEDLRKN128 EDKLNHHQRI138 GLKYFGDFEK148 RIPREEMLQM158 QDIVLNEVKK 168 VDSEYIATVC178 GSFRRGAESS188 GDMDVLLTHP198 SFTSESTKQP208 KLLHQVVEQL 218 QKVHFITDTL228 SKGETKFMGV238 CQLPSKNDEK248 EYPHRRIDIR258 LIPKDQYYCG 268 VLYFTGSDIF278 NKNMRAHALE288 KGFTINEYTI298 RPLGVTGVAG308 EPLPVDSEKD 318 IFDYIQWKYR328 EPKDRSE
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| Ligand Name: Cisplatin | Ligand Info | |||||
| Structure Description | Human DNA polymerase beta inserting dCMPNPP opposite the 5'G of cisplatin crosslinked Gs (Pt-GG2) | PDB:4TUR | ||||
| Method | X-ray diffraction | Resolution | 2.17 Å | Mutation | No | [4] |
| PDB Sequence |
PQETLNGGIT
16 DMLTELANFE26 KNVSQAIHKY36 NAYRKAASVI46 AKYPHKIKSG56 AEAKKLPGVG 66 TKIAEKIDEF76 LATGKLRKLE86 KIRQDDTSSS96 INFLTRVSGI106 GPSAARKFVD 116 EGIKTLEDLR126 KNEDKLNHHQ136 RIGLKYFGDF146 EKRIPREEML156 QMQDIVLNEV 166 KKVDSEYIAT176 VCGSFRRGAE186 SSGDMDVLLT196 HPSFTSESQP208 KLLHQVVEQL 218 QKVHFITDTL228 SKGETKFMGV238 CQLPSKNDEK248 EYPHRRIDIR258 LIPKDQYYCG 268 VLYFTGSDIF278 NKNMRAHALE288 KGFTINEYTI298 RPLGVTGVAG308 EPLPVDSEKD 318 IFDYIQWKYR328 EPKDRSE
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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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| Base excision repair | hsa03410 | Affiliated Target |
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| Class: Genetic Information Processing => Replication and repair | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 3.59E-05 |
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| Closeness centrality | 2.06E-01 | Radiality | 1.36E+01 | Clustering coefficient | 5.00E-01 |
| Neighborhood connectivity | 2.53E+01 | Topological coefficient | 1.81E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | FF-10502, an Antimetabolite with Novel Activity on Dormant Cells, Is Superior to Gemcitabine for Targeting Pancreatic Cancer Cells. J Pharmacol Exp Ther. 2018 Jul;366(1):125-135. | |||||
| REF 2 | ClinicalTrials.gov (NCT02661542) Study of FF-10502-01 in Patients With Advanced Solid Tumors and Lymphomas. U.S. National Institutes of Health. | |||||
| REF 3 | A structural basis for metal ion mutagenicity and nucleotide selectivity in human DNA polymerase beta. Biochemistry. 1996 Oct 1;35(39):12762-77. | |||||
| REF 4 | Structural basis for the inefficient nucleotide incorporation opposite cisplatin-DNA lesion by human DNA polymerase beta. J Biol Chem. 2014 Nov 7;289(45):31341-8. | |||||
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