Target Information

Target General Information

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Target ID

T98691

Target Name

HUMAN cathepsin L (CTSL)

Synonyms

Major excreted protein; MEP; Cathepsin L1; CTSL1

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Gene Name

CTSL

Disease

[+] 2 Target-related Diseases

Middle East Respiratory Syndrome [ICD-11: 1D64]

Severe acute respiratory syndrome [ICD-11: 1D65]

Function

Important for the overall degradation of proteins in lysosomes.

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BioChemical Class

Peptidase

UniProt ID

CATL1_HUMAN

EC Number

EC 3.4.22.15

Sequence

MNPTLILAAFCLGIASATLTFDHSLEAQWTKWKAMHNRLYGMNEEGWRRAVWEKNMKMIE
LHNQEYREGKHSFTMAMNAFGDMTSEEFRQVMNGFQNRKPRKGKVFQEPLFYEAPRSVDW
REKGYVTPVKNQGQCGSCWAFSATGALEGQMFRKTGRLISLSEQNLVDCSGPQGNEGCNG
GLMDYAFQYVQDNGGLDSEESYPYEATEESCKYNPKYSVANDTGFVDIPKQEKALMKAVA
TVGPISVAIDAGHESFLFYKEGIYFEPDCSSEDMDHGVLVVGYGFESTESDNNKYWLVKN
SWGEEWGMGGYVKMAKDRRNHCGIASAASYPTV

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

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Preclinical Drugs

[+] 3

E-64D

Drug Info

Preclinical

Severe acute respiratory syndrome (SARS)

[1], [2]

K11777

Drug Info

Preclinical

Severe acute respiratory syndrome (SARS)

[1], [3]

PMID26868298-compound-5705213

Drug Info

Preclinical

Severe acute respiratory syndrome (SARS)

[1], [4]

Mode of Action

[+] 1 Modes of Action

Blocker

[+] 3 Blocker drugs

E-64D

Drug Info

[1], [2]

K11777

Drug Info

[1], [3]

PMID26868298-compound-5705213

Drug Info

[1], [4]

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: 3-Sulfinoalanine

Ligand Info

Structure Description

Exploring inhibitor binding at the S subsites of cathepsin L

PDB:3BC3

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[5]

PDB Sequence

APRSVDWREK

¹⁰

GYVTPVKNQG

²⁰

QCGSWAFSAT

³¹

GALEGQMFRK

⁴¹

TGRLISLSEQ

⁵¹

NLVDCSGPQG

⁶¹

NEGCNGGLMD

⁷¹

YAFQYVQDNG

⁸¹

GLDSEESYPY

⁹¹

EATEESCKYN

¹⁰¹

PKYSVANDTG

¹¹¹

FVDIPKQEKA

¹²¹

LMKAVATVGP

¹³¹

ISVAIDAGHE

¹⁴¹

SFLFYKEGIY

¹⁵¹

FEPDCSSEDM

¹⁶¹

DHGVLVVGYG

¹⁷¹

FESNKYWLVK

¹⁸⁶

NSWGEEWGMG

¹⁹⁶

GYVKMAKDRR

²⁰⁶

NHCGIASAAS

²¹⁶

YPTV

Residue

Distance (Å)

GLN19

3.119

CYS22

4.486

GLY23

3.482

SER24

1.330

TRP26

1.330

ALA27

3.061

PHE28

3.097

Residue

Distance (Å)

SER29

2.853

ALA30

4.769

ASP162

3.473

HIS163

3.029

GLY164

2.838

SER188

4.160

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

Ligand Name: 1-Propanol

Ligand Info

Structure Description

Structure of mutant human cathepsin L, engineered for GAG binding

PDB:6JD0

Method

X-ray diffraction

Resolution

1.80 Å

Mutation

Yes

[6]

PDB Sequence

TLTFDHSLEA

¹⁰

QWTKWKAMHN

²⁰

RLYGMNEEGW

³⁰

RRAVWEKNMK

⁴⁰

MIELHNQEYR

⁵⁰

EGKHSFTMAM

⁶⁰

NAFGDMTSEE

⁷⁰

FRQVMNGFNR

⁸¹

KPRKGKVFQE

⁹¹

PLFYEAPRSV

¹⁰¹

DWRKKGYVTP

¹¹¹

VKNQGQCGSS

¹²¹

WAFSATGALE

¹³¹

GQMFRKTGRL

¹⁴¹

ISLSEQNLVD

¹⁵¹

CSGPQGNEGC

¹⁶¹

NGGYMDYAFQ

¹⁷¹

YVQDNGGLDS

¹⁸¹

EESYPYEATE

¹⁹¹

ESCKYNPKYS

²⁰¹

VANDTGFVDI

²¹¹

PKQEKALMKA

²²¹

VATVGPISVA

²³¹

IDAGHESFLF

²⁴¹

YKEGIYFEPD

²⁵¹

CSSEDLDHAV

²⁶¹

LVVGYGFEST

²⁷¹

ESNNKYWLVK

²⁸²

NSWGEEWGNK

²⁹²

GYVKMAKDRR

³⁰²

NHCGIASLAS

³¹²

YPTV

Residue

Distance (Å)

GLN11

3.647

LEU22

2.910

VAL34

2.167

LYS37

2.678

ASN38

1.954

MET39

3.332

MET41

3.804

ILE42

2.527

GLU43

3.144

ASN46

4.296

MET58

4.032

ALA59

2.188

MET60

1.932

ASN61

4.770

GLY64

4.844

MET66

3.164

THR67

4.291

SER68

4.269

PHE71

2.567

ARG72

3.238

GLN73

4.360

VAL74

2.207

MET75

1.846

ASN76

1.765

GLY77

3.859

LYS85

3.928

GLY86

2.139

LYS87

1.945

THR110

2.997

PRO111

2.071

VAL112

4.331

LYS113

2.030

ASN114

1.888

GLN115

2.023

CYS118

3.264

GLY119

1.850

SER120

2.378

SER121

1.566

TRP122

2.259

Residue

Distance (Å)

ALA123

4.588

PHE124

2.851

PHE135

3.651

GLY139

3.010

ARG140

2.206

LEU141

1.808

ILE142

2.944

SER143

2.280

GLU146

4.614

ASN162

4.671

GLY163

2.977

GLY164

4.708

GLN171

2.685

GLN174

2.512

GLU182

2.961

TYR187

2.871

THR206

3.311

GLY207

2.273

PHE208

2.020

VAL209

4.979

LYS213

2.643

ALA234

4.669

GLY235

2.384

HIS236

3.756

GLU237

2.295

LEU240

2.326

PHE241

3.043

SER254

2.182

GLU255

2.404

ASP258

2.664

HIS259

2.583

ALA260

3.772

TRP285

3.988

GLY286

4.942

ARG302

4.210

ASN303

1.755

GLY306

4.291

ALA308

4.815

SER309

3.090

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Putative inactive cathepsin L-like protein CTSL3P (CTSL3P)		67.273 (74/110)	1.68E-42


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
Autophagy - animal	hsa04140	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Lysosome	hsa04142	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Phagosome	hsa04145	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Antigen processing and presentation	hsa04612	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	2.36E-05
Closeness centrality	1.70E-01	Radiality	1.27E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	6.33E+00	Topological coefficient	3.56E-01	Eccentricity	14
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

Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.

REF 2

The Cysteine Protease Inhibitor, E64d, Reduces Brain Amyloid- and Improves Memory Deficits in Alzheimer's Disease Animal Models by Inhibiting Cathepsin B, but Not BACE1, -Secretase Activity. J Alzheimers Dis. 2011;26(2):387-408.

REF 3

Protease Inhibitors Targeting Coronavirus and Filovirus Entry. Antiviral Res. 2015 Apr;116:76-84.

REF 4

Identification of a Broad-Spectrum Antiviral Small Molecule Against Severe Acute Respiratory Syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by Using a Novel High-Throughput Screening Assay. J Virol. 2014 Apr;88(8):4353-65.

REF 5

Exploring inhibitor binding at the S' subsites of cathepsin L. J Med Chem. 2008 Mar 13;51(5):1361-8.

REF 6

Structure-guided protein engineering of human cathepsin L for efficient collagenolytic activity. Protein Eng Des Sel. 2021 Feb 15;34:gzab005.

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