Target Information

Target General Information

Target ID

T43814

Target Name

Toll/interleukin-1 receptor domain-containing adapter (TIRAP)

Synonyms

Toll/interleukin-1 receptor domain-containing adapter protein; TIR domain-containing adapter protein; MyD88-2; MyD88 adapter-like protein; MAL; Adaptor protein Wyatt

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Gene Name

TIRAP

Target Type

Patented-recorded target

[1]

Function

Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6. Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response.

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UniProt ID

TIRAP_HUMAN

Sequence

MASSTSLPAPGSRPKKPLGKMADWFRQTLLKKPKKRPNSPESTSSDASQPTSQDSPLPPS
LSSVTSPSLPPTHASDSGSSRWSKDYDVCVCHSEEDLVAAQDLVSYLEGSTASLRCFLQL
RDATPGGAIVSELCQALSSSHCRVLLITPGFLQDPWCKYQMLQALTEAPGAEGCTIPLLS
GLSRAAYPPELRFMYYVDGRGPDGGFRQVKEAVMRYLQTLS

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3D Structure

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AlphaFold

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: (2S,3S)-1,4-Dimercaptobutane-2,3-diol

Ligand Info

Structure Description

S180L variant of TIR domain of Mal/TIRAP

PDB:3UB4

Method

X-ray diffraction

Resolution

3.10 Å

Mutation

[2]

PDB Sequence

SSRWSKDYDV

⁸⁸

CVCHSEEDLV

⁹⁸

AAQDLVSYLE

¹⁰⁸

GAIVSELCQA

¹³⁶

LSSSHCRVLL

¹⁴⁶

ITPGFLQDPW

¹⁵⁶

CKYQMLQALT

¹⁶⁶

EAPGAEGCTI

¹⁷⁶

PLLLGLSRAA

¹⁸⁶

YPPELRFMYY

¹⁹⁶

VDGRGPDGGF

²⁰⁶

RQVKEAVMRY

²¹⁶

LQTLS

Residue

Distance (Å)

VAL90

4.666

CYS91

3.110

HIS92

2.772

SER93

3.301

GLU94

4.768

CYS134

3.155

Residue

Distance (Å)

GLN135

4.684

ARG143

4.301

PHE151

4.460

TRP156

3.153

CYS157

2.925

GLN160

3.721

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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 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 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 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 Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Myeloid differentiation primary response protein MyD88 (MYD88)	PF00531 ; PF01582	25.786 (41/159)	1.27E-08
Toll-like receptor 2 (TLR2)	PF13855 ; PF01463 ; PF01582 More >>	31.169 (24/77)	1.16E-06
Toll-like receptor 6 (TLR6)	PF13855 ; PF01463 ; PF01582 More >>	28.767 (21/73)	3.15E-05
Toll-like receptor 1 (TLR1)	PF13855 ; PF01463 ; PF01582 More >>	29.545 (13/44)	2.00E-03
Toll-like receptor 10 (TLR10)	PF00560 ; PF13855 ; PF01582 More >>	26.389 (19/72)	4.00E-03
Toll-like receptor 5 (TLR5)	PF13855 ; PF01582	29.213 (26/89)	4.00E-03
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KEGG Pathway	Pathway ID	Affiliated Target
NF-kappa B signaling pathway	hsa04064	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	11	Degree centrality	1.18E-03	Betweenness centrality	4.49E-06
Closeness centrality	2.19E-01	Radiality	1.38E+01	Clustering coefficient	8.00E-01
Neighborhood connectivity	2.91E+01	Topological coefficient	2.02E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target