Target Information

Target General Information

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Target ID

T08583 (Former ID: TTDR00395)

Target Name

Thrombomodulin (THBD)

Synonyms

TM; THRM; Fetomodulin; CD141 antigen; CD141

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Gene Name

THBD

Target Type

Discontinued target

[1]

Disease

[+] 1 Target-related Diseases

Disseminated intravascular coagulation [ICD-11: 3B20]

Function

Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated.

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BioChemical Class

Growth factor

UniProt ID

TRBM_HUMAN

Sequence

MLGVLVLGALALAGLGFPAPAEPQPGGSQCVEHDCFALYPGPATFLNASQICDGLRGHLM
TVRSSVAADVISLLLNGDGGVGRRRLWIGLQLPPGCGDPKRLGPLRGFQWVTGDNNTSYS
RWARLDLNGAPLCGPLCVAVSAAEATVPSEPIWEEQQCEVKADGFLCEFHFPATCRPLAV
EPGAAAAAVSITYGTPFAARGADFQALPVGSSAAVAPLGLQLMCTAPPGAVQGHWAREAP
GAWDCSVENGGCEHACNAIPGAPRCQCPAGAALQADGRSCTASATQSCNDLCEHFCVPNP
DQPGSYSCMCETGYRLAADQHRCEDVDDCILEPSPCPQRCVNTQGGFECHCYPNYDLVDG
ECVEPVDPCFRANCEYQCQPLNQTSYLCVCAEGFAPIPHEPHRCQMFCNQTACPADCDPN
TQASCECPEGYILDDGFICTDIDECENGGFCSGVCHNLPGTFECICGPDSALARHIGTDC
DSGKVDGGDSGSGEPPPSPTPGSTLTPPAVGLVHSGLLIGISIASLCLVVALLALLCHLR
KKQGAARAKMEYKCAAPSKEVVLQHVRTERTPQRL

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3D Structure

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AlphaFold

ADReCS ID

BADD_A00503 ; BADD_A04284 ; BADD_A04982

HIT2.0 ID

T73HTV

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
C-type lectin domain family 14 member A (CLEC14A)		27.675 (75/271)	6.80E-09
Sushi, nidogen and EGF-like domain-containing protein 1 (SNED1)	PF00008 ; PF00041 ; PF12661 ; PF06119 More >>	29.297 (75/256)	9.43E-07
Protein eyes shut homolog (EYS)	PF00008 ; PF12661 ; PF00054 ; PF02210 More >>	29.651 (51/172)	1.13E-06
Protocadherin Fat 1 (FAT1)	PF00028 ; PF00008 ; PF02210 More >>	25.221 (57/226)	3.14E-06
Protein crumbs homolog 2 (CRB2)	PF00008 ; PF12661 ; PF02210 More >>	27.897 (65/233)	3.97E-06
Slit homolog 1 protein (SLIT1)	PF00008 ; PF12661 ; PF02210 ; PF13855 ; PF01463 ; PF01462 More >>	30.542 (62/203)	5.46E-06
Delta and Notch-like epidermal growth factor-related receptor (DNER)	PF19330 ; PF00008 ; PF12661 More >>	28.866 (56/194)	2.55E-05
Protein crumbs homolog 1 (CRB1)	PF00008 ; PF12661 ; PF02210 More >>	31.053 (59/190)	4.26E-05
Stabilin-2 (STAB2)	PF12947 ; PF02469 ; PF00193 More >>	26.882 (75/279)	5.99E-05
Protocadherin Fat 3 (FAT3)	PF00028 ; PF02210	28.696 (33/115)	1.00E-03
Coagulation factor VII (F7)	PF00008 ; PF00594 ; PF00089 More >>	43.750 (21/48)	5.00E-03
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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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Complement and coagulation cascades	hsa04610	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	4.23E-06
Closeness centrality	1.79E-01	Radiality	1.29E+01	Clustering coefficient	6.67E-01
Neighborhood connectivity	1.38E+01	Topological coefficient	3.62E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Complement and coagulation cascades

Panther Pathway

[+] 1 Panther Pathways

Blood coagulation

PID Pathway

[+] 1 PID Pathways

Validated transcriptional targets of AP1 family members Fra1 and Fra2

Reactome

[+] 2 Reactome Pathways

Common Pathway of Fibrin Clot Formation

Cell surface interactions at the vascular wall

WikiPathways

[+] 5 WikiPathways

Complement and Coagulation Cascades

Nuclear Receptors Meta-Pathway

Vitamin D Receptor Pathway

Formation of Fibrin Clot (Clotting Cascade)

Cell surface interactions at the vascular wall

References

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REF 1

Thrombomodulin. Nihon Yakurigaku Zasshi. 2000 Nov;116(5):283-9.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002139)

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