Target Information
| Target General Information | Top | |||||
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| Target ID |
T64074
(Former ID: TTDC00341)
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| Target Name |
Scavenger decapping enzyme DcpS (DCPS)
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| Synonyms |
Scavenger mRNA-decapping enzyme DcpS; Histidine triad protein member5; Hint-related 7meGMP-directed hydrolase; HINT-5; DCS-1; DCPS
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| Gene Name |
DCPS
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Muscular atrophy [ICD-11: 8B61] | |||||
| Function |
Decapping scavenger enzyme that catalyzes the cleavage of a residual cap structure following the degradation of mRNAs by the 3'->5' exosome-mediated mRNA decay pathway. Hydrolyzes cap analog structures like 7-methylguanosine nucleoside triphosphate (m7GpppG) with up to 10 nucleotide substrates (small capped oligoribonucleotides) and specifically releases 5'-phosphorylated RNA fragments and 7-methylguanosine monophosphate (m7GMP). Cleaves cap analog structures like tri-methyl guanosine nucleoside triphosphate (m3(2,2,7)GpppG) with very poor efficiency. Does not hydrolyze unmethylated cap analog (GpppG) and shows no decapping activity on intact m7GpppG-capped mRNA molecules longer than 25 nucleotides. Does not hydrolyze 7-methylguanosine diphosphate (m7GDP) to m7GMP (PubMed:22985415). May also play a role in the 5'->3 mRNA decay pathway; m7GDP, the downstream product released by the 5'->3' mRNA mediated decapping activity, may be also converted by DCPS to m7GMP (PubMed:14523240). Binds to m7GpppG and strongly to m7GDP. Plays a role in first intron splicing of pre- mRNAs. Inhibits activation-induced cell death.
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| BioChemical Class |
Acid anhydrides hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.6.1.59
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| Sequence |
MADAAPQLGKRKRELDVEEAHAASTEEKEAGVGNGTCAPVRLPFSGFRLQKVLRESARDK
IIFLHGKVNEASGDGDGEDAVVILEKTPFQVEQVAQLLTGSPELQLQFSNDIYSTYHLFP PRQLNDVKTTVVYPATEKHLQKYLRQDLRLIRETGDDYRNITLPHLESQSLSIQWVYNIL DKKAEADRIVFENPDPSDGFVLIPDLKWNQQQLDDLYLIAICHRRGIRSLRDLTPEHLPL LRNILHQGQEAILQRYRMKGDHLRVYLHYLPSYYHLHVHFTALGFEAPGSGVERAHLLAE VIENLECDPRHYQQRTLTFALRADDPLLKLLQEAQQS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | RG3039 | Drug Info | Phase 1 | Spinal muscular atrophy | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | RG3039 | 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: 7-Methyl-Gpppa | Ligand Info | |||||
| Structure Description | Structure of DcpS bound to m7GpppA | PDB:1ST4 | ||||
| Method | X-ray diffraction | Resolution | 2.02 Å | Mutation | Yes | [2] |
| PDB Sequence |
VRLPFSGFRL
49 QKVLRESARD59 KIIFLHGKVN69 EASGDGDGED79 AVVILEKTPF89 QVEQVAQLLT 99 GSPELQLQFS109 NDIYSTYHLF119 PPRQLNDVKT129 TVVYPATEKH139 LQKYLRQDLR 149 LIRETGDDYR159 NITLPHLESQ169 SLSIQWVYNI179 LDKKAEADRI189 VFENPDPSDG 199 FVLIPDLKWN209 QQQLDDLYLI219 AICHRRGIRS229 LRDLTPEHLP239 LLRNILHQGQ 249 EAILQRYRMK259 GDHLRVYLHY269 LPSYYHLNVH279 FTALGFEAPG289 SGVERAHLLA 299 EVIENLECDP309 RHYQQRTLTF319 ALRADDPLLK329 LLQEAQQ
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LEU144
4.152
ARG145
3.107
GLN146
2.894
LEU148
3.899
TRP175
3.153
ILE179
4.163
GLU185
2.663
ARG188
4.221
ILE203
3.743
PRO204
3.163
ASP205
2.684
LEU206
3.594
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| Ligand Name: 7-Methyl-guanosine-5'-triphosphate-5'-guanosine | Ligand Info | |||||
| Structure Description | Structure of DcpS bound to m7GpppG | PDB:1ST0 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [2] |
| PDB Sequence |
VRLPFSGFRL
49 QKVLRESARD59 KIIFLHGKVN69 EASGDGDGED79 AVVILEKTPF89 QVEQVAQLLT 99 GSPELQLQFS109 NDIYSTYHLF119 PPRQLNDVKT129 TVVYPATEKH139 LQKYLRQDLR 149 LIRETGDDYR159 NITLPHLESQ169 SLSIQWVYNI179 LDKKAEADRI189 VFENPDPSDG 199 FVLIPDLKWN209 QQQLDDLYLI219 AICHRRGIRS229 LRDLTPEHLP239 LLRNILHQGQ 249 EAILQRYRMK259 GDHLRVYLHY269 LPSYYHLNVH279 FTALGFEAPG289 SGVERAHLLA 299 EVIENLECDP309 RHYQQRTLTF319 ALRADDPLLK329 LLQEAQQ
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LEU144
4.806
ARG145
3.604
GLN146
4.277
TRP175
3.229
ILE179
4.063
GLU185
2.857
ARG188
3.510
ILE203
3.629
PRO204
3.157
ASP205
2.638
LEU206
3.448
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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).
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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| RNA degradation | hsa03018 | Affiliated Target |
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| Class: Genetic Information Processing => Folding, sorting and degradation | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 4.52E-05 |
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| Closeness centrality | 1.57E-01 | Radiality | 1.23E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.25E+01 | Topological coefficient | 5.00E-01 | Eccentricity | 14 |
| 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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | RNA degradation | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Deadenylation-dependent mRNA decay | |||||
| References | Top | |||||
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| REF 1 | 2011 Pipeline of Repligen. | |||||
| REF 2 | Insights into the structure, mechanism, and regulation of scavenger mRNA decapping activity. Mol Cell. 2004 Apr 9;14(1):67-80. | |||||
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