Target Information

Target General Information

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Target ID

T00442

Target Name

HUMAN catechol-O-methyl-transferase (COMT)

Synonyms

S-COMT; MB-COMT; Catechol-O-methyltransferase; COMT

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Gene Name

COMT

Function

Human protein catechol-O-methyltransferase interacts with SARS-CoV-2 Nsp7 protein with high significance, which indicates COMT as a potential therapeutic target.

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BioChemical Class

Methyltransferase

UniProt ID

COMT_HUMAN

EC Number

EC 2.1.1.6

Sequence

MPEAPPLLLAAVLLGLVLLVVLLLLLRHWGWGLCLIGWNEFILQPIHNLLMGDTKEQRIL
NHVLQHAEPGNAQSVLEAIDTYCEQKEWAMNVGDKKGKIVDAVIQEHQPSVLLELGAYCG
YSAVRMARLLSPGARLITIEINPDCAAITQRMVDFAGVKDKVTLVVGASQDIIPQLKKKY
DVDTLDMVFLDHWKDRYLPDTLLLEECGLLRKGTVLLADNVICPGAPDFLAHVRGSSCFE
CTHYQSFLEYREVVDGLEKAIYKGPGSEAGP

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3D Structure

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PDB

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: Ademetionine

Ligand Info

Structure Description

Crystal Structure of Human 108M Catechol O-methyltransferase bound with S-adenosylmethionine and inhibitor dinitrocatechol

PDB:3BWY

Method

X-ray diffraction

Resolution

1.30 Å

Mutation

[2]

PDB Sequence

GDTKEQRILN

¹¹

HVLQHAEPGN

²¹

AQSVLEAIDT

³¹

YCEQKEWAMN

⁴¹

VGDKKGKIVD

⁵¹

AVIQEHQPSV

⁶¹

LLELGAYCGY

⁷¹

SAVRMARLLS

⁸¹

PGARLITIEI

⁹¹

NPDCAAITQR

¹⁰¹

MVDFAGMKDK

¹¹¹

VTLVVGASQD

¹²¹

IIPQLKKKYD

¹³¹

VDTLDMVFLD

¹⁴¹

HWKDRYLPDT

¹⁵¹

LLLEECGLLR

¹⁶¹

KGTVLLADNV

¹⁷¹

ICPGAPDFLA

¹⁸¹

HVRGSSCFEC

¹⁹¹

THYQSFLEYR

²⁰¹

EVVDGLEKAI

²¹¹

YKGP

Residue

Distance (Å)

MET40

3.440

ASN41

3.721

VAL42

2.838

GLU64

3.935

GLY66

2.904

ALA67

3.582

TYR68

3.324

GLY70

4.543

TYR71

3.248

SER72

2.751

ILE89

3.692

GLU90

2.670

ILE91

3.221

Residue

Distance (Å)

ASN92

4.020

CYS95

4.187

GLY117

3.684

ALA118

3.581

SER119

2.876

GLN120

3.136

PHE139

3.836

ASP141

2.681

HIS142

3.585

TRP143

3.380

LYS144

4.457

ARG146

3.916

ASP150

4.988

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Sinefungin

Ligand Info

Structure Description

Crystal structure of Human soluble catechol O-methyltransferase in complex with 3,5-dinitrocatechol and Sinefungin

PDB:6I3D

Method

X-ray diffraction

Resolution

1.45 Å

Mutation

[3]

PDB Sequence

GDTKEQRILN

¹¹

HVLQHAEPGN

²¹

AQSVLEAIDT

³¹

YCEQKEWAMN

⁴¹

VGDKKGKIVD

⁵¹

AVIQEHQPSV

⁶¹

LLELGAYCGY

⁷¹

SAVRMARLLS

⁸¹

PGARLITIEI

⁹¹

NPDCAAITQR

¹⁰¹

MVDFAGVKDK

¹¹¹

VTLVVGASQD

¹²¹

IIPQLKKKYD

¹³¹

VDTLDMVFLD

¹⁴¹

HWKDRYLPDT

¹⁵¹

LLLEECGLLR

¹⁶¹

KGTVLLADNV

¹⁷¹

ICPGAPDFLA

¹⁸¹

HVRGSSCFEC

¹⁹¹

THYQSFLEYR

²⁰¹

EVVDGLEKAI

²¹¹

YKGP

Residue

Distance (Å)

MET40

3.367

ASN41

3.669

VAL42

2.841

GLU64

3.962

LEU65

4.995

GLY66

2.875

ALA67

3.530

TYR68

3.208

GLY70

4.489

TYR71

3.302

SER72

2.746

ILE89

3.591

GLU90

2.655

ILE91

3.247

Residue

Distance (Å)

ASN92

3.784

CYS95

3.933

GLY117

3.715

ALA118

3.733

SER119

2.938

GLN120

3.202

PHE139

3.906

ASP141

2.722

HIS142

3.494

TRP143

3.337

LYS144

4.513

ARG146

4.315

ASP150

4.932

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). 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

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).

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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target
Steroid hormone biosynthesis	hsa00140	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Tyrosine metabolism	hsa00350	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Dopaminergic synapse	hsa04728	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

Degree	7	Degree centrality	7.52E-04	Betweenness centrality	5.35E-04
Closeness centrality	1.75E-01	Radiality	1.28E+01	Clustering coefficient	2.38E-01
Neighborhood connectivity	5.71E+00	Topological coefficient	2.09E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

References

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REF 1

A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug Repurposing. Nature. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9.

REF 2

Crystal structures of human 108V and 108M catechol O-methyltransferase. J Mol Biol. 2008 Jun 27;380(1):120-30.

REF 3

Equatorial Active Site Compaction and Electrostatic Reorganization in Catechol-O-methyltransferase. ACS Catal. 2019 May 3;9(5):4394-4401.

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