Target Information
| Target General Information | Top | |||||
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| Target ID |
T32973
(Former ID: TTDI02612)
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| Target Name |
Legumain (LGMN)
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| Synonyms |
Protease, cysteine 1; PRSC1; Asparaginyl endopeptidase
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| Gene Name |
LGMN
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Can also cleave aspartyl bonds slowly, especially under acidic conditions. Required for normal lysosomal protein degradation in renal proximal tubules. Required for normal degradation of internalized EGFR. Plays a role in the regulation of cell proliferation via its role in EGFR degradation. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system. Has a strict specificity for hydrolysis of asparaginyl bonds.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.22.34
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| Sequence |
MVWKVAVFLSVALGIGAVPIDDPEDGGKHWVVIVAGSNGWYNYRHQADACHAYQIIHRNG
IPDEQIVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVTPQNFLAVLRGD AEAVKGIGSGKVLKSGPQDHVFIYFTDHGSTGILVFPNEDLHVKDLNETIHYMYKHKMYR KMVFYIEACESGSMMNHLPDNINVYATTAANPRESSYACYYDEKRSTYLGDWYSVNWMED SDVEDLTKETLHKQYHLVKSHTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVT HLDLTPSPDVPLTIMKRKLMNTNDLEESRQLTEEIQRHLDARHLIEKSVRKIVSLLAASE AEVEQLLSERAPLTGHSCYPEALLHFRTHCFNWHSPTYEYALRHLYVLVNLCEKPYPLHR IKLSMDHVCLGHY 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 | Legumain-cleavable doxorubicin prodrugs | Drug Info | Phase 2/3 | Solid tumour/cancer | [2] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Legumain-cleavable doxorubicin prodrugs | Drug Info | [1] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | PMID24775305C7u | Drug Info | [3] | |||
| 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: (3S)-3-Aminopyrrolidine-2,5-dione | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF YVAD-CMK BOUND HUMAN LEGUMAIN (AEP) IN COMPLEX WITH COMPOUND 11B | PDB:5LU8 | ||||
| Method | X-ray diffraction | Resolution | 1.95 Å | Mutation | Yes | [4] |
| PDB Sequence |
GGKHWVVIVA
35 GSNGWYNYRH45 QADACHAYQI55 IHRNGIPDEQ65 IVVMMYDDIA75 YSEDNPTPGI 85 VINRPNGTDV95 YQGVPKDYTG105 EDVTPQNFLA115 VLRGDAEAVK125 GIGSGKVLKS 135 GPQDHVFIYF145 THGSTGILVF156 PNEDLHVKDL166 NETIHYMYKH176 KMYRKMVFYI 186 EACESGSMMN196 HLPDNINVYA206 TTAANPRESS216 YACYYDEKRS226 TYLGDWYSVN 236 WMEDSDVEDL246 TKETLHKQYH256 LVKSHTQTSH266 VMQYGNKTIS276 TMKVMQFQGM 286 KR
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2,4-Di-morpholin-4-yl-phenylamine | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF YVAD-CMK BOUND HUMAN LEGUMAIN (AEP) IN COMPLEX WITH COMPOUND 11B | PDB:5LU8 | ||||
| Method | X-ray diffraction | Resolution | 1.95 Å | Mutation | Yes | [4] |
| PDB Sequence |
GGKHWVVIVA
35 GSNGWYNYRH45 QADACHAYQI55 IHRNGIPDEQ65 IVVMMYDDIA75 YSEDNPTPGI 85 VINRPNGTDV95 YQGVPKDYTG105 EDVTPQNFLA115 VLRGDAEAVK125 GIGSGKVLKS 135 GPQDHVFIYF145 THGSTGILVF156 PNEDLHVKDL166 NETIHYMYKH176 KMYRKMVFYI 186 EACESGSMMN196 HLPDNINVYA206 TTAANPRESS216 YACYYDEKRS226 TYLGDWYSVN 236 WMEDSDVEDL246 TKETLHKQYH256 LVKSHTQTSH266 VMQYGNKTIS276 TMKVMQFQGM 286 KR
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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 | ||
| Antigen processing and presentation | hsa04612 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.07E-04 | Radiality | 3.98E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+00 | Topological coefficient | . | Eccentricity | 1 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Lysosome | |||||
| 2 | Antigen processing and presentation | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Trafficking and processing of endosomal TLR | |||||
| 2 | Vitamin D (calciferol) metabolism | |||||
| 3 | MHC class II antigen presentation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Metabolism of steroid hormones and vitamin D | |||||
| 2 | MHC class II antigen presentation | |||||
| References | Top | |||||
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| REF 1 | 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: 2380). | |||||
| REF 2 | ClinicalTrials.gov (NCT01442636) Drug Eluting Stents In The Critically Ischemic Lower Leg 2. U.S. National Institutes of Health. | |||||
| REF 3 | P3 SAR exploration of biphenyl carbamate based Legumain inhibitors. Bioorg Med Chem Lett. 2014 Jun 1;24(11):2521-4. | |||||
| REF 4 | Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. Nat Commun. 2017 Mar 27;8:14740. | |||||
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