Target Information
| Target General Information | Top | |||||
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| Target ID |
T79031
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| Target Name |
Beta-secretase 1 (BACE1)
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| Synonyms |
Membrane-associated aspartic protease 2; Memapsin-2; KIAA1149; Beta-site amyloid precursor protein cleaving enzyme 1; Beta-site APP cleaving enzyme 1; BACE; Aspartyl protease 2; Asp 2; ASP2
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| Gene Name |
BACE1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Alzheimer disease [ICD-11: 8A20] | |||||
| Function |
Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Cleaves APP with much more catalytic efficiency than for the wild-type. Responsible for the proteolytic processing of the amyloid precursor protein (APP).
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.23.46
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| Sequence |
MAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSF
VEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSST YRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGIL GLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGI DHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKK VFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRIT ILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSAC HVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQW RCLRCLRQQHDDFADDISLLK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T04H8Y | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | E-2609 | Drug Info | Phase 3 | Alzheimer disease | [1], [2] | |
| 2 | verubecestat | Drug Info | Phase 3 | Alzheimer disease | [1] | |
| 3 | AMG520 | Drug Info | Phase 2/3 | Alzheimer disease | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | E-2609 | Drug Info | [1], [2] | |||
| 2 | verubecestat | Drug Info | [1] | |||
| 3 | AMG520 | Drug Info | [1] | |||
| 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: Urea | Ligand Info | |||||
| Structure Description | Crystal structure of bace1 with novel inhibitor | PDB:4FGX | ||||
| Method | X-ray diffraction | Resolution | 1.59 Å | Mutation | Yes | [3] |
| PDB Sequence |
GSFVEMVDNL
54 RGKSGQGYYV64 EMTVGSPPQT74 LNILVDTGSS84 NFAVGAAPHP94 FLHRYYQRQL 104 SSTYRDLRKG114 VYVPYTQGAW124 AGELGTDLVS134 IPHGPNVTVR144 ANIAAITESD 154 KFFINGSNWE164 GILGLAYAEI174 ARPDDSLEPF184 FDSLVKQTHV194 PNLFSLQLCG 204 ASVGGSMIIG225 GIDHSLYTGS235 LWYTPIRREW245 YYEVIIVRVE255 INGQDLKMDC 265 KEYNYDKSIV275 DSGTTNLRLP285 KKVFEAAVKS295 IKAASSTEKF305 PDGFWLGEQL 315 VCWQAGTTPW325 NIFPVISLYL335 MGEVTNQSFR345 ITILPQQYLR355 PVESQDDCYK 369 FAISQSSTGT379 VMGAVIMEGF389 YVVFDRARKR399 IGFAVSACHV409 HDEFRTAAVE 419 GPFVTLDMED429 CGYNI
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: JNJ-54861911 | Ligand Info | |||||
| Structure Description | Crystal Structure of BACE1 in complex with N-{3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4- fluorophenyl}-5-cyanopyridine-2-carboxamide | PDB:7DCZ | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [4] |
| PDB Sequence |
RGSFVEMVDN
5 LRGKSGQGYY15 VEMTVGSPPQ25 TLNILVDTGS35 SNFAVGAAPH45 PFLHRYYQRQ 55 LSSTYRDLRK65 GVYVPYTQGK75 WEGELGTDLV85 SIPHGPNVTV95 RANIAAITES 105 DKFFINGSNW115 EGILGLAYAE125 IARPDDSLEP135 FFDSLVKQTH145 VPNLFSLQLC 155 GAASVGGSMI175 IGGIDHSLYT185 GSLWYTPIRR195 EWYYEVIIVR205 VEINGQDLKM 215 DCKEYNYDKS225 IVDSGTTNLR235 LPKKVFEAAV245 KSIKAASSTE255 KFPDGFWLGE 265 QLVCWQGTTP276 WNIFPVISLY286 LMGEVTNQSF296 RITILPQQYL306 RPVEDVATSQ 316 DDCYKFAISQ326 SSTGTVMGAV336 IMEGFYVVFD346 RARKRIGFAV356 SACHVHDEFR 366 TAAVEGPFVT376 LDMEDCGYN
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GLY11
3.600
GLN12
3.497
GLY13
3.199
TYR14
4.031
LEU30
3.441
ASP32
2.893
GLY34
3.564
SER35
3.940
TYR71
3.086
PHE108
3.430
ILE110
3.819
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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).
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
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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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| Degree | 8 | Degree centrality | 8.59E-04 | Betweenness centrality | 4.24E-04 |
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| Closeness centrality | 2.08E-01 | Radiality | 1.36E+01 | Clustering coefficient | 1.43E-01 |
| Neighborhood connectivity | 1.41E+01 | Topological coefficient | 1.60E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Alzheimer disease | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Cyanobacterial peptides as a prototype for the design of potent beta-secretase inhibitors and the development of selective chemical probes for other aspartic proteases. J Med Chem. 2012 Dec 13;55(23):10749-65. | |||||
| REF 4 | Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based beta-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial. J Med Chem. 2021 Feb 25;64(4):1873-1888. | |||||
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