Target Information
| Target General Information | Top | |||||
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| Target ID |
T01280
(Former ID: TTDI03051)
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| Target Name |
Beta-site APP-cleaving enzyme 2 (BACE2)
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| Synonyms |
Theta-secretase; Membrane-associated aspartic protease 1; Memapsin-1; Down region aspartic protease; DRAP; Beta-site amyloid precursor protein cleaving enzyme 2; Beta-site APP cleaving enzyme 2; Beta-secretase 2; Aspartyl protease 1; Aspartic-like protease 56 kDa; Asp 1; ASP21; ASP1; ALP56; AEPLC
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| Gene Name |
BACE2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Urinary system clinical sympton [ICD-11: MF8Y] | |||||
| Function |
Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading 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. It has also been shown that it can cleave APP between residues 671 and 672. Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells.
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| UniProt ID | ||||||
| EC Number |
EC 3.4.23.45
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| Sequence |
MGALARALLLPLLAQWLLRAAPELAPAPFTLPLRVAAATNRVVAPTPGPGTPAERHADGL
ALALEPALASPAGAANFLAMVDNLQGDSGRGYYLEMLIGTPPQKLQILVDTGSSNFAVAG TPHSYIDTYFDTERSSTYRSKGFDVTVKYTQGSWTGFVGEDLVTIPKGFNTSFLVNIATI FESENFFLPGIKWNGILGLAYATLAKPSSSLETFFDSLVTQANIPNVFSMQMCGAGLPVA GSGTNGGSLVLGGIEPSLYKGDIWYTPIKEEWYYQIEILKLEIGGQSLNLDCREYNADKA IVDSGTTLLRLPQKVFDAVVEAVARASLIPEFSDGFWTGSQLACWTNSETPWSYFPKISI YLRDENSSRSFRITILPQLYIQPMMGAGLNYECYRFGISPSTNALVIGATVMEGFYVIFD RAQKRVGFAASPCAEIAGAAVSEISGPFSTEDVASNCVPAQSLSEPILWIVSYALMSVCG AILLVLIVLLLLPFRCQRRPRDPEVVNDESSLVRHRWK 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 | example 98 (WO2011020806) | Drug Info | Clinical trial | Focal segmental glomerulosclerosis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 7 Inhibitor drugs | + | ||||
| 1 | example 98 (WO2011020806) | Drug Info | [1] | |||
| 2 | 2ewy | Drug Info | [3] | |||
| 3 | example 2 (WO2013004676) | Drug Info | [4] | |||
| 4 | example 20 (WO2010128058) | Drug Info | [5] | |||
| 5 | example 41 (WO2012028563) | Drug Info | [5] | |||
| 6 | example 92 (WO2012095521) | Drug Info | [5] | |||
| 7 | PMID21907142CJ | Drug Info | [6] | |||
| 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: Verubecestat | Ligand Info | |||||
| Structure Description | BACE2 xaperone complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-5,6-dihydro-2H-1lambda6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide | PDB:7D5B | ||||
| Method | X-ray diffraction | Resolution | 1.31 Å | Mutation | No | [7] |
| PDB Sequence |
ANFLAMVDNL
22 QGDSGRGYYL32 EMLIGTPPQK42 LQILVDTGSS52 NFAVAGTPHS62 YIDTYFDTER 72 SSTYRSKGFD82 VTVKYTQGSW92 TGFVGEDLVT102 IPKGFNTSFL112 VNIATIFESE 122 NFFLPGIKWN132 GILGLAYATL142 AKPSSSLETF152 FDSLVTQANI162 PNVFSMQMCG 172 AGLNGGSLVL189 GGIEPSLYKG199 DIWYTPIKEE209 WYYQIEILKL219 EIGGQSLNLD 229 CREYNADKAI239 VDSGTTLLRL249 PQKVFDAVVE259 AVARASLIPE269 FSDGFWTGSQ 279 LACWTNTPWS291 YFPKISIYLR301 DENSSRSFRI311 TILPQLYIQP321 MECYRFGISP 338 STNALVIGAT348 VMEGFYVIFD358 RAQKRVGFAA368 SPCAEIAGAA378 VSEISGPFST 388 EDVASNCVP
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| Ligand Name: 2ewy | Ligand Info | |||||
| Structure Description | Crystal structure of human BACE2 in complex with a hydroxyethylenamine transition-state inhibitor | PDB:2EWY | ||||
| Method | X-ray diffraction | Resolution | 3.10 Å | Mutation | No | [3] |
| PDB Sequence |
LAMVDNLQGD
25 SGRGYYLEML35 IGTPPQKLQI45 LVDTGSSNFA55 VAGTPHSYID65 TYFDTERSST 75 YRSKGFDVTV85 KYTQGSWTGF95 VGEDLVTIPK105 GFNTSFLVNI115 ATIFESENFF 125 LPGIKWNGIL135 GLAYATLAKP145 SSSLETFFDS155 LVTQANIPNV165 FSMQMCGANG 184 GSLVLGGIEP194 SLYKGDIWYT204 PIKEEWYYQI214 EILKLEIGGQ224 SLNLDCREYN 234 ADKAIVDSGT244 TLLRLPQKVF254 DAVVEAVARA264 SLIPEFSDGF274 WTGSQLACWT 284 NSETPWSYFP294 KISIYLRDEN304 SSRSFRITIL314 PQLYIQPMMG324 AGLNYECYRF 334 GISPSTNALV344 IGATVMEGFY354 VIFDRAQKRV364 GFAASPCAEI374 AGAAVSEISG 384 PFSTEDVASN394 CVPA
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LEU46
3.528
ASP48
2.748
GLY50
3.062
SER51
3.635
VAL85
4.390
LYS86
3.154
TYR87
3.496
THR88
3.126
GLN89
3.622
ASN123
4.840
PHE124
3.466
LEU126
4.172
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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 Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | BACE2 as a new diabetes target: a patent review (2010 - 2012). Expert Opin Ther Pat. 2013 May;23(5):649-63. | |||||
| REF 2 | 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. (Ligand id: 6540). | |||||
| REF 3 | Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. J Mol Biol. 2006 Jan 13;355(2):249-61. | |||||
| REF 4 | Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors. ACS Med Chem Lett. 2013 Mar 15;4(4):379-80. | |||||
| REF 5 | 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: 2331). | |||||
| REF 6 | Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 2011 Sep 7;14(3):365-77. | |||||
| REF 7 | Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2. J Med Chem. 2021 Mar 25;64(6):3075-3085. | |||||
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