Target Information
| Target General Information | Top | |||||
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| Target ID |
T37154
(Former ID: TTDNC00448)
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| Target Name |
Cathepsin A (CTSA)
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| Synonyms |
Protective protein for betagalactosidase; Protective protein cathepsin A; PPCA; Lysosomal protective protein 20 kDa chain; Lysosomal protective protein; Carboxypeptidase L; Carboxypeptidase C; CTSA
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| Gene Name |
CTSA
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Acute diabete complication [ICD-11: 5A2Y] | |||||
| Function |
Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.16.5
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| Sequence |
MIRAAPPPLFLLLLLLLLLVSWASRGEAAPDQDEIQRLPGLAKQPSFRQYSGYLKGSGSK
HLHYWFVESQKDPENSPVVLWLNGGPGCSSLDGLLTEHGPFLVQPDGVTLEYNPYSWNLI ANVLYLESPAGVGFSYSDDKFYATNDTEVAQSNFEALQDFFRLFPEYKNNKLFLTGESYA GIYIPTLAVLVMQDPSMNLQGLAVGNGLSSYEQNDNSLVYFAYYHGLLGNRLWSSLQTHC CSQNKCNFYDNKDLECVTNLQEVARIVGNSGLNIYNLYAPCAGGVPSHFRYEKDTVVVQD LGNIFTRLPLKRMWHQALLRSGDKVRMDPPCTNTTAASTYLNNPYVRKALNIPEQLPQWD MCNFLVNLQYRRLYRSMNSQYLKLLSSQKYQILLYNGDVDMACNFMGDEWFVDSLNQKME VQRRPWLVKYGDSGEQIAGFVKEFSHIAFLTIKGAGHMVPTDKPLAAFTMFSRFLNKQPY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | SAR164653 | Drug Info | Phase 1 | Diabetic complication | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | SAR164653 | Drug Info | [1] | |||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | example 166 (WO2014154727) | Drug Info | [3] | |||
| 2 | PMID22861813C8a | Drug Info | [4] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: PMID22861813C8a | Ligand Info | |||||
| Structure Description | crystal structure of cathepsin a, complexed with 8a. | PDB:4AZ0 | ||||
| Method | X-ray diffraction | Resolution | 2.17 Å | Mutation | No | [4] |
| PDB Sequence |
> Chain A
RAPDQDEIQR 9 LPGLAKQPSF19 RQYSGYLKGS29 GSKHLHYWFV39 ESQKDPENSP49 VVLWLNGGPG 59 CSSLDGLLTE69 HGPFLVQPDG79 VTLEYNPYSW89 NLIANVLYLE99 SPAGVGFSYS 109 DDKFYATNDT119 EVAQSNFEAL129 QDFFRLFPEY139 KNNKLFLTGE149 SYAGIYIPTL 159 AVLVMQDPSM169 NLQGLAVGNG179 LSSYEQNDNS189 LVYFAYYHGL199 LGNRLWSSLQ 209 THCCSQNKCN219 FYDNKDLECV229 TNLQEVARIV239 GNSGLNIYNL249 YAPCAGGVPS 259 > Chain B PPCTNTTAAS 310 TYLNNPYVRK320 ALNIPEQLPQ330 WDMCNFLVNL340 QYRRLYRSMN350 SQYLKLLSSQ 360 KYQILLYNGD370 VDMACNFMGD380 EWFVDSLNQK390 MEVQRRPWLV400 KYGDSGEQIA 410 GFVKEFSHIA420 FLTIKGAGHM430 VPTDKPLAAF440 TMFSRFLNKQ450 PYE |
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ASN55[A]
2.765
GLY56[A]
2.795
GLY57[A]
3.670
PRO58[A]
3.582
GLY59[A]
4.768
CYS60[A]
3.400
SER61[A]
4.927
ASP64[A]
3.491
GLU149[A]
2.669
SER150[A]
3.579
TYR247[A]
3.323
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| Ligand Name: 2-(cyclohexylmethyl)propanedioic Acid | Ligand Info | |||||
| Structure Description | crystal structure of cathepsin a, complexed with compound 2 | PDB:4CIB | ||||
| Method | X-ray diffraction | Resolution | 1.89 Å | Mutation | No | [5] |
| PDB Sequence |
RAPDQDEIQR
9 LPGLAKQPSF19 RQYSGYLKGS29 GSKHLHYWFV39 ESQKDPENSP49 VVLWLNGGPG 59 CSSLDGLLTE69 HGPFLVQPDG79 VTLEYNPYSW89 NLIANVLYLE99 SPAGVGFSYS 109 DDKFYATNDT119 EVAQSNFEAL129 QDFFRLFPEY139 KNNKLFLTGE149 SYAGIYIPTL 159 AVLVMQDPSM169 NLQGLAVGNG179 LSSYEQNDNS189 LVYFAYYHGL199 LGNRLWSSLQ 209 THCCSQNKCN219 FYDNKDLECV229 TNLQEVARIV239 GNSGLNIYNL249 YAPCAGGVPS 259 DPPCTNTTAA309 STYLNNPYVR319 KALNIPEQLP329 QWDMCNFLVN339 LQYRRLYRSM 349 NSQYLKLLSS359 QKYQILLYNG369 DVDMACNFMG379 DEWFVDSLNQ389 KMEVQRRPWL 399 VKYGSGEQIA410 GFVKEFSHIA420 FLTIKGAGHM430 VPTDKPLAAF440 TMFSRFLNKQ 450 PYE
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Lysosome | hsa04142 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| Renin-angiotensin system | hsa04614 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 1.15E-08 |
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| Closeness centrality | 1.20E-01 | Radiality | 1.05E+01 | Clustering coefficient | 6.67E-01 |
| Neighborhood connectivity | 4.00E+00 | Topological coefficient | 5.00E-01 | Eccentricity | 14 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Lysosome | |||||
| 2 | Renin-angiotensin system | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Glycosphingolipid metabolism | |||||
| 2 | MHC class II antigen presentation | |||||
| 3 | Sialic acid metabolism | |||||
| References | Top | |||||
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| REF 1 | Tolerability, safety and pharmacokinetics of the novel Cathepsin A inhibitor SAR164653 in healthy subjects.Clinical Pharmacology in Drug Development 05/2015. | |||||
| 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 800035270) | |||||
| REF 3 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1581). | |||||
| REF 4 | Novel beta-amino acid derivatives as inhibitors of cathepsin A. J Med Chem. 2012 Sep 13;55(17):7636-49. | |||||
| REF 5 | Crystal structure of cathepsin A, a novel target for the treatment of cardiovascular diseases. Biochem Biophys Res Commun. 2014 Mar 7;445(2):451-6. | |||||
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