Target Information

Target General Information

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Target ID

T52382 (Former ID: TTDR00927)

Target Name

Lymphocyte antigen 96 (LY96)

Synonyms

MD-2 protein; MD-2; LY96; ESOP-1

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Gene Name

LY96

Target Type

Literature-reported target

[1]

Function

Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria. Enhances TLR4-dependent activation of NF-kappa-B. Cells expressing both MD2 and TLR4, but not TLR4 alone, respond to LPS.

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UniProt ID

LY96_HUMAN

Sequence

MLPFLFFSTLFSSIFTEAQKQYWVCNSSDASISYTYCDKMQYPISINVNPCIELKRSKGL
LHIFYIPRRDLKQLYFNLYITVNTMNLPKRKEVICRGSDDDYSFCRALKGETVNTTISFS
FKGIKFSKGKYKCVVEAISGSPEEMLFCLEFVILHQPNSN

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3D Structure

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PDB

HIT2.0 ID

T15ZAV

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: ERITORAN

Ligand Info

Structure Description

Crystal structure of the human TLR4 TV3 hybrid-MD-2-Eritoran complex

PDB:2Z65

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

[3]

PDB Sequence

QKQYWVCNSS

²⁸

DASISYTYCD

³⁸

KMQYPISINV

⁴⁸

NPCIELKGSK

⁵⁸

GLLHIFYIPR

⁶⁸

RDLKQLYFNL

⁷⁸

YITVNTMNLP

⁸⁸

KRKEVICRGS

⁹⁸

DDDYSFCRAL

¹⁰⁸

KGETVNTTIS

¹¹⁸

FSFKGIKFSK

¹²⁸

GKYKCVVEAI

¹³⁸

SGSPEEMLFC

¹⁴⁸

LEFVILHQPN

¹⁵⁸

Residue

Distance (Å)

ILE32

4.452

ILE46

3.506

VAL48

4.481

ILE52

4.217

LEU54

4.852

LEU61

3.964

ILE63

3.727

TYR65

3.497

LEU71

4.181

LEU74

4.596

PHE76

3.934

LEU78

4.528

ILE80

4.211

LEU87

3.649

ILE94

4.934

TYR102

3.372

PHE104

3.522

Residue

Distance (Å)

VAL113

4.771

ILE117

3.773

SER118

3.776

PHE119

3.335

SER120

2.924

PHE121

3.251

LYS122

4.072

GLY123

3.468

ILE124

4.136

TYR131

4.190

CYS133

3.873

VAL135

4.395

LEU146

4.839

PHE147

4.006

LEU149

4.478

PHE151

3.471

ILE153

4.475

Ligand Name: Myristic acid

Ligand Info

Structure Description

Crystal structure of human MD-2

PDB:2E56

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[4]

PDB Sequence

EAQKQYWVCN

²⁶

SSDASISYTY

³⁶

CDKMQYPISI

⁴⁶

NVNPCIELKG

⁵⁶

SKGLLHIFYI

⁶⁶

PRRDLKQLYF

⁷⁶

NLYITVNTMN

⁸⁶

LPKRKEVICR

⁹⁶

GSDDDYSFCR

¹⁰⁶

ALKGETVNTT

¹¹⁶

ISFSFKGIKF

¹²⁶

SKGKYKCVVE

¹³⁶

AISGSPEEML

¹⁴⁶

FCLEFVILHQ

¹⁵⁶

PNSN

Residue

Distance (Å)

ILE32

4.276

ILE44

4.638

ILE46

4.340

VAL48

3.569

ILE52

3.151

LEU61

3.752

ILE63

4.142

TYR65

4.270

LEU71

4.406

LEU74

4.064

PHE76

4.051

LEU78

4.272

GLU92

3.930

VAL93

4.556

ILE94

4.019

Residue

Distance (Å)

TYR102

4.064

PHE104

3.798

VAL113

4.942

ILE117

4.181

SER118

3.549

PHE119

3.612

SER120

2.843

PHE121

3.939

CYS133

3.816

VAL135

4.268

PHE147

4.273

LEU149

4.483

PHE151

3.892

ILE153

4.387

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

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 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
Lymphocyte antigen 96 (LY96)		100.000 (160/160)	6.55E-119
Lymphocyte antigen 86 (LY86)		24.818 (34/137)	2.32E-05

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	16	Degree centrality	1.72E-03	Betweenness centrality	3.09E-04
Closeness centrality	2.27E-01	Radiality	1.40E+01	Clustering coefficient	3.50E-01
Neighborhood connectivity	2.43E+01	Topological coefficient	1.19E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 5 KEGG Pathways

NF-kappa B signaling pathway

Toll-like receptor signaling pathway

Pathogenic Escherichia coli infection

Pertussis

Toxoplasmosis

NetPath Pathway

[+] 2 NetPath Pathways

TGF_beta_Receptor Signaling Pathway

IL6 Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Toll receptor signaling pathway

PID Pathway

[+] 1 PID Pathways

Endogenous TLR signaling

Reactome

[+] 10 Reactome Pathways

Ligand-dependent caspase activation

Toll Like Receptor 4 (TLR4) Cascade

MyD88:Mal cascade initiated on plasma membrane

MyD88-independent TLR3/TLR4 cascade

TRIF-mediated programmed cell death

MyD88 deficiency (TLR2/4)

IRAK4 deficiency (TLR2/4)

Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon

IKK complex recruitment mediated by RIP1

TRAF6 mediated induction of TAK1 complex

WikiPathways

[+] 6 WikiPathways

Toll-like receptor signaling pathway

Toll-Like Receptors Cascades

MyD88:Mal cascade initiated on plasma membrane

MyD88-independent cascade

Pathogenic Escherichia coli infection

Regulation of toll-like receptor signaling pathway

References

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REF 1

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 2

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 3

Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007 Sep 7;130(5):906-17.

REF 4

Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science. 2007 Jun 15;316(5831):1632-4.

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