Target Information

Target General Information

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Target ID

T71907 (Former ID: TTDI02176)

Target Name

Survival motor neuron protein (SMN1)

Synonyms

SMNT; SMNC; SMN2; SMN; Gemin-1; Component of gems 1

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Gene Name

SMN1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

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

SMN_HUMAN

Sequence

MAMSSGGSGGGVPEQEDSVLFRRGTGQSDDSDIWDDTALIKAYDKAVASFKHALKNGDIC
ETSGKPKTTPKRKPAKKNKSQKKNTAASLQQWKVGDKCSAIWSEDGCIYPATIASIDFKR
ETCVVVYTGYGNREEQNLSDLLSPICEVANNIEQNAQENENESQVSTDESENSRSPGNKS
DNIKPKSAPWNSFLPPPPPMPGPRLGPGKPGLKFNGPPPPPPPPPPHLLSCWLPPFPSGP
PIIPPPPPICPDSLDDADALGSMLISWYMSGYHTGYYMGFRQNQKEGRCSHSLN

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3D Structure

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AlphaFold

HIT2.0 ID

T49V5I ; T71N8B

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Zolgensma

Drug Info

Approved

Spinal muscular atrophy

[2]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

LMI070

Drug Info

Phase 3

Spinal muscular atrophy

[1]

RG7800

Drug Info

Phase 1/2

Spinal muscular atrophy

[3]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 2 Modulator drugs

LMI070

Drug Info

[1]

RG7800

Drug Info

[4]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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

[5]

PDB Sequence

NTAASLQQWK

⁹³

VGDKCSAIWS

¹⁰³

EDGCIYPATI

¹¹³

ASIDFKRETC

¹²³

VVVYTGYGNR

¹³³

EEQNLSDLLS

¹⁴³

PICE

Residue

Distance (Å)

TRP102

2.337

GLU104

4.818

TYR109

2.525

PRO110

4.287

Residue

Distance (Å)

TYR127

2.321

TYR130

2.395

GLY131

4.799

ASN132

1.682

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

[5]

PDB Sequence

NTAASLQQWK

⁹³

VGDKCSAIWS

¹⁰³

EDGCIYPATI

¹¹³

ASIDFKRETC

¹²³

VVVYTGYGNR

¹³³

EEQNLSDLLS

¹⁴³

PICE

Residue

Distance (Å)

TRP102

1.877

GLU104

4.901

ASP105

1.653

TYR109

2.285

PRO110

4.581

Residue

Distance (Å)

TYR127

2.195

TYR130

2.330

GLY131

4.368

ASN132

2.027

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

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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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Tudor domain-containing protein 3 (TDRD3)	PF08585 ; PF00567 ; PF00627 More >>	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.

Degree	15	Degree centrality	1.61E-03	Betweenness centrality	9.63E-06
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

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Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

RNA transport

WikiPathways

[+] 1 WikiPathways

Metabolism of non-coding RNA

References

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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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