Target Information
| Target General Information | Top | |||||
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| Target ID |
T26463
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| Target Name |
DNA polymerase alpha catalytic p180 (POLA1)
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| Synonyms |
POLA; DNA polymerase alpha catalytic subunit p180; DNA polymerase alpha catalytic subunit
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| Gene Name |
POLA1
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| Target Type |
Discontinued target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Virus infection [ICD-11: 1A24-1D9Z] | |||||
| Function |
During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses. Plays an essential role in the initiation of DNA replication.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.7.7
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| Sequence |
MAPVHGDDSLSDSGSFVSSRARREKKSKKGRQEALERLKKAKAGEKYKYEVEDFTGVYEE
VDEEQYSKLVQARQDDDWIVDDDGIGYVEDGREIFDDDLEDDALDADEKGKDGKARNKDK RNVKKLAVTKPNNIKSMFIACAGKKTADKAVDLSKDGLLGDILQDLNTETPQITPPPVMI LKKKRSIGASPNPFSVHTATAVPSGKIASPVSRKEPPLTPVPLKRAEFAGDDVQVESTEE EQESGAMEFEDGDFDEPMEVEEVDLEPMAAKAWDKESEPAEEVKQEADSGKGTVSYLGSF LPDVSCWDIDQEGDSSFSVQEVQVDSSHLPLVKGADEEQVFHFYWLDAYEDQYNQPGVVF LFGKVWIESAETHVSCCVMVKNIERTLYFLPREMKIDLNTGKETGTPISMKDVYEEFDEK IATKYKIMKFKSKPVEKNYAFEIPDVPEKSEYLEVKYSAEMPQLPQDLKGETFSHVFGTN TSSLELFLMNRKIKGPCWLEVKSPQLLNQPVSWCKVEAMALKPDLVNVIKDVSPPPLVVM AFSMKTMQNAKNHQNEIIAMAALVHHSFALDKAAPKPPFQSHFCVVSKPKDCIFPYAFKE VIEKKNVKVEVAATERTLLGFFLAKVHKIDPDIIVGHNIYGFELEVLLQRINVCKAPHWS KIGRLKRSNMPKLGGRSGFGERNATCGRMICDVEISAKELIRCKSYHLSELVQQILKTER VVIPMENIQNMYSESSQLLYLLEHTWKDAKFILQIMCELNVLPLALQITNIAGNIMSRTL MGGRSERNEFLLLHAFYENNYIVPDKQIFRKPQQKLGDEDEEIDGDTNKYKKGRKKAAYA GGLVLDPKVGFYDKFILLLDFNSLYPSIIQEFNICFTTVQRVASEAQKVTEDGEQEQIPE LPDPSLEMGILPREIRKLVERRKQVKQLMKQQDLNPDLILQYDIRQKALKLTANSMYGCL GFSYSRFYAKPLAALVTYKGREILMHTKEMVQKMNLEVIYGDTDSIMINTNSTNLEEVFK LGNKVKSEVNKLYKLLEIDIDGVFKSLLLLKKKKYAALVVEPTSDGNYVTKQELKGLDIV RRDWCDLAKDTGNFVIGQILSDQSRDTIVENIQKRLIEIGENVLNGSVPVSQFEINKALT KDPQDYPDKKSLPHVHVALWINSQGGRKVKAGDTVSYVICQDGSNLTASQRAYAPEQLQK QDNLTIDTQYYLAQQIHPVVARICEPIDGIDAVLIATWLGLDPTQFRVHHYHKDEENDAL LGGPAQLTDEEKYRDCERFKCPCPTCGTENIYDNVFDGSGTDMEPSLYRCSNIDCKASPL TFTVQLSNKLIMDIRRFIKKYYDGWLICEEPTCRNRTRHLPLQFSRTGPLCPACMKATLQ PEYSDKSLYTQLCFYRYIFDAECALEKLTTDHEKDKLKKQFFTPKVLQDYRKLKNTAEQF LSRSGYSEVNLSKLFAGCAVKS 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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| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | HO-221 | Drug Info | Discontinued in Phase 1 | Virus infection | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | HO-221 | 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: Aphidicolin | Ligand Info | |||||
| Structure Description | Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and aphidicolin | PDB:4Q5V | ||||
| Method | X-ray diffraction | Resolution | 2.52 Å | Mutation | Yes | [3] |
| PDB Sequence |
EQVFHFYWLD
347 AYEDQYNQPG357 VVFLFGKVWI367 ESAETHVSCC377 VMVKNIERTL387 YFLPREMKID 397 LNTGKETGTP407 ISMKDVYEEF417 DEKIATKYKI427 MKFKSKPVEK437 NYAFEIPDVP 447 EKSEYLEVKY457 SAEMPQLPQD467 LKGETFSHVF477 GTNTSSLELF487 LMNRKIKGPC 497 WLEVKSPQLL507 NQPVSWCKAE517 AMALKPDLVN527 VIKDVSPPPL537 VVMAFSMKTM 547 QNAKNHQNEI557 IAMAALVHHS567 FALDKAAPKP577 PFQSHFCVVS587 KPKDCIFPYA 597 FKEVIEKKNV607 KVEVAATERT617 LLGFFLAKVH627 KIDPDIIVGH637 NIYGFELEVL 647 LQRINVCKAP657 HWSKIGRLKR667 SNMPKLGFGE681 RNATCGRMIC691 DVEISAKELI 701 RCKSYHLSEL711 VQQILKTERV721 VIPMENIQNM731 YSESSQLLYL741 LEHTWKDAKF 751 ILQIMCELNV761 LPLALQITNI771 AGNIMSRTLM781 GGRSERNEFL791 LLHAFYENNY 801 IVPDKQIRKK836 AAYAGGLVLD846 PKVGFYDKFI856 LLLDFNSLYP866 SIIQEFNICF 876 TTVQRVEQIP899 ELPDPSLEMG909 ILPREIRKLV919 ERRKQVKQLM929 KQQDLNPDLI 939 LQYDIRQKAL949 KLTANSMYGC959 LGFSYSRFYA969 KPLAALVTYK979 GREILMHTKE 989 MVQKMNLEVI999 YGDTDSIMIN1009 TNSTNLEEVF1019 KLGNKVKSEV1029 NKLYKLLEID 1039 IDGVFKSLLL1049 LKKKKYAALV1059 VEPTSDGNYV1069 TKQELKGLDI1079 VRRDWCDLAK 1089 DTGNFVIGQI1099 LSDQSRDTIV1109 ENIQKRLIEI1119 GENVLNGSVP1129 VSQFEINKAL 1139 TKDPQDYPDK1149 KSLPHVHVAL1159 WINSQGGRKV1169 KAGDTVSYVI1179 CQDGSNLTAS 1189 QRAYAPEQLQ1199 KQDNLTIDTQ1209 YYLAQQIHPV1219 VARICEPIDG1229 IDAVLIATWL 1239 GLDPT
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| Ligand Name: 2'-Deoxycytidine-5'-triphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and dCTP | PDB:4QCL | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [4] |
| PDB Sequence |
EQVFHFYWLD
347 AYEDQYNQPG357 VVFLFGKVWI367 ESAETHVSCC377 VMVKNIERTL387 YFLPREMKID 397 LNTGKETGTP407 ISMKDVYEEF417 DEKIATKYKI427 MKFKSKPVEK437 NYAFEIPDVP 447 EKSEYLEVKY457 SAEMPQLPQD467 LKGETFSHVF477 GTNTSSLELF487 LMNRKIKGPC 497 WLEVKSPQLL507 NQPVSWCKAE517 AMALKPDLVN527 VIKDVSPPPL537 VVMAFSMKTM 547 QNAKNHQNEI557 IAMAALVHHS567 FALDKAAPKP577 PFQSHFCVVS587 KPKDCIFPYA 597 FKEVIEKKNV607 KVEVAATERT617 LLGFFLAKVH627 KIDPDIIVGH637 NIYGFELEVL 647 LQRINVCKAP657 HWSKIGRLKR667 SNMPKLGFGE681 RNATCGRMIC691 DVEISAKELI 701 RCKSYHLSEL711 VQQILKTERV721 VIPMENIQNM731 YSESSQLLYL741 LEHTWKDAKF 751 ILQIMCELNV761 LPLALQITNI771 AGNIMSRTLM781 GGRSERNEFL791 LLHAFYENNY 801 IVPDKQIRKK836 AAYAGGLVLD846 PKVGFYDKFI856 LLLDFNSLYP866 SIIQEFNICF 876 TTVQRVEQIP899 ELPDPSLEMG909 ILPREIRKLV919 ERRKQVKQLM929 KQQDLNPDLI 939 LQYDIRQKAL949 KLTANSMYGC959 LGFSYSRFYA969 KPLAALVTYK979 GREILMHTKE 989 MVQKMNLEVI999 YGDTDSIMIN1009 TNSTNLEEVF1019 KLGNKVKSEV1029 NKLYKLLEID 1039 IDGVFKSLLL1049 LKKKKYAALV1059 VEPTSDGNYV1069 TKQELKGLDI1079 VRRDWCDLAK 1089 DTGNFVIGQI1099 LSDQSRDTIV1109 ENIQKRLIEI1119 GENVLNGSVP1129 VSQFEINKAL 1139 TKDPQDYPDK1149 KSLPHVHVAL1159 WINSQGGRKV1169 KAGDTVSYVI1179 CQDGSNLTAS 1189 QRAYAPEQLQ1199 KQDNLTIDTQ1209 YYLAQQIHPV1219 VARICEPIDG1229 IDAVLIATWL 1239 GLDPT
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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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| DNA replication | hsa03030 | Affiliated Target |
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| Class: Genetic Information Processing => Replication and repair | Pathway Hierarchy | ||
| Degree | 44 | Degree centrality | 4.73E-03 | Betweenness centrality | 1.44E-04 |
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| Closeness centrality | 2.13E-01 | Radiality | 1.37E+01 | Clustering coefficient | 4.36E-01 |
| Neighborhood connectivity | 3.59E+01 | Topological coefficient | 1.26E-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-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Effect of novel benzoylphenylurea derivatives on DNA polymerase alpha activity using the synthesome-based in vitro model system. Invest New Drugs. 2003 Nov;21(4):421-8. | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000797) | |||||
| REF 3 | Structural basis for inhibition of DNA replication by aphidicolin. Nucleic Acids Res. 2014 Dec 16;42(22):14013-21. | |||||
| REF 4 | Activity and fidelity of human DNA polymerase alpha depend on primer structure | |||||
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