Target Information

Target General Information

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Target ID

T53612 (Former ID: TTDR01120)

Target Name

Kallikrein-6 (KLK6)

Synonyms

Zyme; Serine protease 9; Serine protease 18; SP59; Protease M; PRSS9; PRSS18; Neurosin; MSP; K6

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Gene Name

KLK6

Target Type

Literature-reported target

[1]

Function

Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis. Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position.

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BioChemical Class

Peptidase

UniProt ID

KLK6_HUMAN

EC Number

EC 3.4.21.-

Sequence

MKKLMVVLSLIAAAWAEEQNKLVHGGPCDKTSHPYQAALYTSGHLLCGGVLIHPLWVLTA
AHCKKPNLQVFLGKHNLRQRESSQEQSSVVRAVIHPDYDAASHDQDIMLLRLARPAKLSE
LIQPLPLERDCSANTTSCHILGWGKTADGDFPDTIQCAYIHLVSREECEHAYPGQITQNM
LCAGDEKYGKDSCQGDSGGPLVCGDHLRGLVSWGNIPCGSKEKPGVYTNVCRYTNWIQKT
IQAK

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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: Benzamidine

Ligand Info

Structure Description

Human Kallikrein 6 (hK6) active form with benzamidine inhibitor at 1.56 A resolution

PDB:1LO6

Method

X-ray diffraction

Resolution

1.56 Å

Mutation

[3]

PDB Sequence

LVHGGPCDKT

²⁵

SHPYQAALYT

³⁵

SGHLLCGGVL

⁴⁶

IHPLWVLTAA

⁵⁶

HCKKPNLQVF

⁶⁶

LGKHNLRQRE

⁷⁷

SSQEQSSVVR

⁸⁷

AVIHPDYDAA

⁹⁷

SHDQDIMLLR

¹⁰⁷

LARPAKLSEL

¹¹⁷

IQPLPLERDC

¹²⁸

SANTTSCHIL

¹³⁹

GWGKTADGDF

¹⁵¹

PDTIQCAYIH

¹⁶¹

LVSREECEHA

¹⁷¹

YPGQITQNML

¹⁸¹

CAGDEKYGKD

¹⁸⁹

SCQGDSGGPL

¹⁹⁹

VCGDHLRGLV

²¹³

SWGNIPCGSK

²²²

EKPGVYTNVC

²³²

RYTNWIQKTI

²⁴²

Residue

Distance (Å)

ASP189

2.938

SER190

2.968

CYS191

3.940

GLN192

4.195

SER195

3.979

VAL213

3.717

SER214

3.778

TRP215

3.563

Residue

Distance (Å)

GLY216

3.619

ASN217

2.947

ILE218

4.280

CYS220

3.860

GLY220A

4.666

GLY226

3.695

VAL227

4.596

TYR228

4.735

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

Ligand Name: 6-[5-[(3aS,4R,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-N-[(2R)-1-[[(2S)-3-cyclohexyl-1-[[(2S)-1-[[(1R)-4-(diaminomethylideneamino)-1-diphenoxyphosphorylbutyl]amino]-3-[(3S)-2,3-dihydro-1H-indol-3-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]hexanamide

Ligand Info

Structure Description

Crystal structure of KLK6 in complex with compound 16a

PDB:7QFT

Method

X-ray diffraction

Resolution

1.47 Å

Mutation

Yes

[4]

PDB Sequence

LVHGGPCDKT

²⁵

SHPYQAALYT

³⁵

SGHLLCGGVL

⁴⁶

IHPLWVLTAA

⁵⁶

HCKKPNLQVF

⁶⁶

LGKHNLGQQE

⁷⁷

SSQEQSSVVR

⁸⁷

AVIHPDYDAA

⁹⁷

SHDQDIMLLR

¹⁰⁷

LARPAKLSEL

¹¹⁷

IQPLPLERDC

¹²⁸

SAQTTSCHIL

¹³⁹

GWGKTADGDF

¹⁵¹

PDTIQCAYIH

¹⁶¹

LVSREECEHA

¹⁷¹

YPGQITQNML

¹⁸¹

CAGDEKYGKD

¹⁸⁹

SCQGDSGGPL

¹⁹⁹

VCGDHLRGLV

²¹³

SWGNIPCGSK

²²²

EKPGVYTNVC

²³²

RYTNWIQKTI

²⁴²

Residue

Distance (Å)

LEU41

3.230

CYS42

3.842

HIS57

2.883

TYR94

3.228

ALA96

3.853

HIS99

3.064

ASP102

4.207

TYR172

3.577

GLN175

4.357

ASP189

2.777

SER190

2.735

CYS191

3.544

GLN192

3.551

GLY193

2.639

Residue

Distance (Å)

ASP194

3.297

SER195

1.693

VAL213

3.780

SER214

2.981

TRP215

3.413

GLY216

2.889

ASN217

2.930

ILE218

3.268

PRO219

4.851

CYS220

3.819

GLY220A

4.353

LYS224

3.671

GLY226

3.830

VAL227

4.829

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

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.

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.98E-01	Radiality	1.34E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	3.50E+01	Topological coefficient	1.00E+00	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 Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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NetPath Pathway

[+] 1 NetPath Pathways

IL1 Signaling Pathway

PID Pathway

[+] 1 PID Pathways

Alpha-synuclein signaling

WikiPathways

[+] 2 WikiPathways

Vitamin D Receptor Pathway

Hair Follicle Development: Cytodifferentiation (Part 3 of 3)

References

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REF 1

Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group. ACS Med Chem Lett. 2012 Jan 11;3(2):159-64.

REF 2

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

REF 3

Crystal structure and biochemical characterization of human kallikrein 6 reveals a

REF 4

Crystal structure of KLK6 in complex with compound 16a

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