Target Information
Target General Information | Top | |||||
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Target ID |
T71907
(Former ID: TTDI02176)
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Target Name |
Survival motor neuron protein (SMN1)
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Synonyms |
SMNT; SMNC; SMN2; SMN; Gemin-1; Component of gems 1
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Gene Name |
SMN1
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Muscular atrophy [ICD-11: 8B61] | |||||
Function |
Thereby, plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP. In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. Dissociation by the SMN complex of CLNS1A from the trapped Sm proteins and their transfer to an SMN-Sm complex triggers the assembly of core snRNPs and their transport to the nucleus. Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development. Also required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs). The SMN complex plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome.
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UniProt ID | ||||||
Sequence |
MAMSSGGSGGGVPEQEDSVLFRRGTGQSDDSDIWDDTALIKAYDKAVASFKHALKNGDIC
ETSGKPKTTPKRKPAKKNKSQKKNTAASLQQWKVGDKCSAIWSEDGCIYPATIASIDFKR ETCVVVYTGYGNREEQNLSDLLSPICEVANNIEQNAQENENESQVSTDESENSRSPGNKS DNIKPKSAPWNSFLPPPPPMPGPRLGPGKPGLKFNGPPPPPPPPPPHLLSCWLPPFPSGP PIIPPPPPICPDSLDDADALGSMLISWYMSGYHTGYYMGFRQNQKEGRCSHSLN Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T49V5I ; T71N8B |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | LMI070 | Drug Info | Phase 3 | Spinal muscular atrophy | [1] | |
2 | RG7800 | Drug Info | Phase 1/2 | Spinal muscular atrophy | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | LMI070 | Drug Info | [1] | |||
2 | RG7800 | Drug Info | [4] |
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: N,N-dimethylarginine | Ligand Info | |||||
Structure Description | Solution structure of SMN Tudor domain in complex with asymmetrically dimethylated arginine | PDB:4A4G | ||||
Method | Solution NMR | Resolution | N.A. | Mutation | No | [5] |
PDB Sequence |
NTAASLQQWK
93 VGDKCSAIWS103 EDGCIYPATI113 ASIDFKRETC123 VVVYTGYGNR133 EEQNLSDLLS 143 PICE
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Ligand Name: SDMA | Ligand Info | |||||
Structure Description | Solution structure of SMN Tudor domain in complex with symmetrically dimethylated arginine | PDB:4A4E | ||||
Method | Solution NMR | Resolution | N.A. | Mutation | No | [5] |
PDB Sequence |
NTAASLQQWK
93 VGDKCSAIWS103 EDGCIYPATI113 ASIDFKRETC123 VVVYTGYGNR133 EEQNLSDLLS 143 PICE
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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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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Tudor domain-containing protein 3 (TDRD3) | 38.462 (20/52) | 7.06E-05 |
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 | 15 | Degree centrality | 1.61E-03 | Betweenness centrality | 9.63E-06 |
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Closeness centrality | 1.91E-01 | Radiality | 1.33E+01 | Clustering coefficient | 8.38E-01 |
Neighborhood connectivity | 5.62E+01 | Topological coefficient | 3.85E-01 | Eccentricity | 13 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
1 | RNA transport | |||||
WikiPathways | [+] 1 WikiPathways | + | ||||
1 | Metabolism of non-coding RNA |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. | |||||
REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800039744) | |||||
REF 4 | Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy. Assay Drug Dev Technol. 2014 August 1; 12(6): 315-341. | |||||
REF 5 | Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. Nat Struct Mol Biol. 2011 Nov 20;18(12):1414-20. |
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