Target Information
| Target General Information | Top | |||||
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| Target ID |
T32369
(Former ID: TTDI01569)
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| Target Name |
Influenza Polymerase acidic endonuclease (Influ PA)
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| Synonyms |
RNA-directed RNA polymerase subunit P2; Polymerase acidic protein
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| Gene Name |
Influ PA
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Influenza [ICD-11: 1E30-1E32] | |||||
| Function |
Plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits. The complex transcribes viral mRNAs by using a unique mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. These short capped RNAs are then used as primers for viral mRNAs. The PB2 subunit is responsible for the binding of the 5' cap of cellular pre-mRNAs which are subsequently cleaved after 10-13 nucleotides by the PA subunit that carries the endonuclease activity.
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| UniProt ID | ||||||
| EC Number |
EC 3.1.-.-
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| Sequence |
MEDFVRQCFNPMIVELAEKTMKEYGEDLKIETNKFAAICTHLEVCFMYSDFHFINEQGES
IIVELGDPNALLKHRFEIIEGRDRTMAWTVVNSICNTTGAEKPKFLPDLYDYKENRFIEI GVTRREVHIYYLEKANKIKSEKTHIHIFSFTGEEMATKADYTLDEESRARIKTRLFTIRQ EMASRGLWDSFRQSERGEETIEERFEITGTMRKLADQSLPPNFSSLENFRAYVDGFEPNG YIEGKLSQMSKEVNARIEPFLKTTPRPLRLPNGPPCSQRSKFLLMDALKLSIEDPSHEGE GIPLYDAIKCMRTFFGWKEPNVVKPHEKGINPNYLLSWKQVLAELQDIENEEKIPKTKNM KKTSQLKWALGENMAPEKVDFDDCKDVGDLKQYDSDEPELRSLASWIQNEFNKACELTDS SWIELDEIGEDVAPIEHIASMRRNYFTSEVSHCRATEYIMKGVYINTALLNASCAAMDDF QLIPMISKCRTKEGRRKTNLYGFIIKGRSHLRNDTDVVNFVSMEFSLTDPRLEPHKWEKY CVLEIGDMLIRSAIGQVSRPMFLYVRTNGTSKIKMKWGMEMRRCLLQSLQQIESMIEAES SVKEKDMTKEFFENKSETWPIGESPKGVEESSIGKVCRTLLAKSVFNSLYASPQLEGFSA ESRKLLLIVQALRDNLEPGTFDLGGLYEAIEECLINDPWVLLNASWFNSFLTHALS Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Baloxavir marboxil | Drug Info | Approved | Influenza virus infection | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Baloxavir marboxil | Drug Info | [1] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 4-{(E)-[2-(4-Chlorophenyl)hydrazinylidene]methyl}benzene-1,2,3-Triol | Ligand Info | |||||
| Structure Description | Endonuclease inhibitor bound to influenza strain H1N1 polymerase acidic subunit N-terminal region without a chelation to the metal ions in the active site | PDB:4ZI0 | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [2] |
| PDB Sequence |
GPLGSMEDFV
5 RQCFNPMIVE15 LAEKTMKEYG25 EDLKIETNKF35 AAICTHLEVC45 FMYSDASKHR 75 FEIIEGRDRT85 MAWTVVNSIC95 NTTGAEKPKF105 LPDLYDYKEN115 RFIEIGVTRR 125 EVHIYYLEKA135 NKIKSEKTHI145 HIFSFTGEEM155 ATKADYTLDE165 ESRARIKTRL 175 FTIRQEMASR185 GLWDSFRQSE195 R
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2-(4-Fluorophenoxy)-1-(2,3,4-trihydroxyphenyl)ethanone | Ligand Info | |||||
| Structure Description | Phenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonuclease | PDB:4YYL | ||||
| Method | X-ray diffraction | Resolution | 1.91 Å | Mutation | No | [3] |
| PDB Sequence |
GPLGSMEDFV
5 RQCFNPMIVE15 LAEKTMKEYG25 EDLKIETNKF35 AAICTHLEVC45 FMYSDASKHR 75 FEIIEGRDRT85 MAWTVVNSIC95 NTTGAEKPKF105 LPDLYDYKEN115 RFIEIGVTRR 125 EVHIYYLEKA135 NKIKSEKTHI145 HIFSFTGEEM155 ATKADYTLDE165 ESRARIKTRL 175 FTIRQEMASR185 GLWDSFRQSE195 R
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THR20
3.236
TYR24
3.386
GLU26
3.205
ILE30
4.397
GLU31
3.006
ASN33
3.886
LYS34
3.218
ALA37
2.687
ILE38
3.089
HIS41
3.177
GLU80
3.002
ARG84
2.937
TRP88
4.313
LYS104
4.746
PHE105
3.676
LEU106
3.155
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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 Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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| 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 | ||||||
| References | Top | |||||
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| REF 1 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 2 | Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit. Biochemistry. 2016 May 10;55(18):2646-60. | |||||
| REF 3 | Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase. Bioorg Med Chem. 2015 Sep 1;23(17):5466-75. | |||||
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