Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T01280 | Target Info | |||
| Target Name | Beta-site APP-cleaving enzyme 2 (BACE2) | ||||
| 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 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | BACE2 | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| 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 | [1] |
| 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 | [2] |
| 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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| Ligand Name: (3S)-3-hydroxy-N-(2-methylpropyl)-N~2~-{[(4S)-17-[(methylsulfonyl)(propyl)amino]-2-oxo-3-azatricyclo[13.3.1.1~6,10~]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}-L-norleucinamide | Ligand Info | |||||
| Structure Description | BACE2 mutant in complex with a macrocyclic compound | PDB:6UJ1 | ||||
| Method | X-ray diffraction | Resolution | 3.03 Å | Mutation | Yes | [3] |
| PDB Sequence |
LAMVDNLQGD
25 SGRGYYLEML35 IGTPPQKLQI45 LVDTGSSNFA55 VAGTPHSYID65 TYFDTERSST 75 YRSKGFDVTV85 KYTQGSWTGF95 VGEDLVTIPK105 GFNTSFLVNI115 ATIFESENFF 125 LPGIKWNGIL135 GLAYATLAKP145 SSSLETFFDS155 LVTQANIPNV165 FSMQMCGAGL 175 PGTNGGSLVL189 GGIEPSLYKG199 DIWYTPIKEE209 WYYQIEILKL219 EIGGQSLNLD 229 CREYNADKAI239 VDSGTTLLRL249 PQKVFDAVVE259 AVARASFSDG273 FWTGSQLACW 283 TNSETPWSYF293 PKISIYLRDE303 NSSRSFRITI313 LPQLYIQPML327 NYECYRFGIS 337 PSTNALVIGA347 TVMEGFYVIF357 DRAQKRVGFA367 ASPCAEIAGA377 AVSEISGPFS 387 TASNCVP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .L3M or .L3M2 or .L3M3 or :3L3M;style chemicals stick;color identity;select .A:27 or .A:28 or .A:46 or .A:48 or .A:50 or .A:51 or .A:85 or .A:86 or .A:87 or .A:88 or .A:89 or .A:124 or .A:126 or .A:131 or .A:134 or .A:142 or .A:211 or .A:239 or .A:241 or .A:243 or .A:244 or .A:245 or .A:246 or .A:248 or .A:337 or .A:342 or .A:344; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLY27
4.131
ARG28
4.248
LEU46
4.225
ASP48
3.352
GLY50
3.108
SER51
4.041
VAL85
3.871
LYS86
3.108
TYR87
3.422
THR88
2.260
GLN89
3.443
PHE124
3.623
LEU126
4.601
TRP131
4.049
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| Ligand Name: N-{3-[(2S,5R)-6-amino-2-(fluoromethyl)-5-(methanesulfonyl)-5-methyl-2,3,4,5-tetrahydropyridin-2-yl]-4-fluorophenyl}-6-methoxypyrimidine-4-carboxamide | Ligand Info | |||||
| Structure Description | BACE-2 in complex with ligand 36 | PDB:7N4N | ||||
| Method | X-ray diffraction | Resolution | 1.41 Å | Mutation | No | [4] |
| PDB Sequence |
ANFLAMVDNL
22 QGDSGRGYYL32 EMLIGTPPQK42 LQILVDTGSS52 NFAVAGTPHS62 YIDTYFDTER 72 SSTYRSKGFD82 VTVKYTQGSW92 TGFVGEDLVT102 IPKGFNTSFL112 VNIATIFESE 122 NFFLPGIKWN132 GILGLAYATL142 AKPSSSLETF152 FDSLVTQANI162 PNVFSMQMCG 172 AGGGSLVLGG191 IEPSLYKGDI201 WYTPIKEEWY211 YQIEILKLEI221 GGQSLNLDCR 231 EYNADKAIVD241 SGTTLLRLPQ251 KVFDAVVEAV261 ARASLIPEFS271 DGFWTGSQLA 281 CWTWSYFPKI296 SIYLRDENSS306 RSFRITILPQ316 LYIQPMYECY332 RFGISPSTNA 342 LVIGATVMEG352 FYVIFDRAQK362 RVGFAASPCA372 EIAGAAVSEI382 SGPFSTEDVA 392 SNCVPA
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .0BK or .0BK2 or .0BK3 or :30BK;style chemicals stick;color identity;select .A:27 or .A:28 or .A:29 or .A:30 or .A:46 or .A:48 or .A:49 or .A:50 or .A:51 or .A:85 or .A:87 or .A:88 or .A:89 or .A:92 or .A:124 or .A:126 or .A:129 or .A:131 or .A:134 or .A:142 or .A:170 or .A:211 or .A:239 or .A:241 or .A:242 or .A:243 or .A:244 or .A:245 or .A:344 or .A:347 or .A:351; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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GLY27
2.294
ARG28
3.008
GLY29
2.807
TYR30
3.517
LEU46
2.806
ASP48
1.946
THR49
5.000
GLY50
2.588
SER51
2.622
VAL85
4.845
TYR87
2.511
THR88
4.427
GLN89
4.944
TRP92
4.032
PHE124
2.419
LEU126
4.949
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| Ligand Name: N-[3-[(4R,5R,6R)-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxamide | Ligand Info | |||||
| Structure Description | BACE2 xaperone complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide | PDB:7F1G | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [5] |
| PDB Sequence |
ANFLAMVDNL
22 QGDGRGYYLE33 MLIGTPPQKL43 QILVDTGSSN53 FAVAGTPHSY63 IDTYFDTERS 73 STYRSKGFDV83 TVKYTQGSWT93 GFVGEDLVTI103 PKGFNTSFLV113 NIATIFESEN 123 FFLKWNGILG136 LAYATLAKPS146 SSLETFFDSL156 VTQANIPNVF166 SMQMCGANGG 185 SLVLGGIEPS195 LYKGDIWYTP205 IKEEWYYQIE215 ILKLEIGGQS225 LNLDCREYNA 235 DKAIVDSGTT245 LLRLPQKVFD255 AVVEAVARAS265 LIPEFSDGFW275 TGSQLACWTT 288 PWSYFPKISI298 YLRDENSSRS308 FRITILPQLY318 IQPMECYRFG335 ISPSTNALVI 345 GATVMEGFYV355 IFDRAQKRVG365 FAASPCAEIA375 GAAVSEISGP385 FSTEDVASNC 395 VP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .0QQ or .0QQ2 or .0QQ3 or :30QQ;style chemicals stick;color identity;select .A:25 or .A:27 or .A:28 or .A:29 or .A:30 or .A:46 or .A:48 or .A:49 or .A:50 or .A:51 or .A:85 or .A:87 or .A:88 or .A:89 or .A:92 or .A:123 or .A:124 or .A:126 or .A:131 or .A:134 or .A:170 or .A:211 or .A:241 or .A:242 or .A:243 or .A:244 or .A:245 or .A:333 or .A:347 or .A:351; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ASP25
2.566
GLY27
2.354
ARG28
2.957
GLY29
2.439
TYR30
2.754
LEU46
2.873
ASP48
1.875
THR49
4.969
GLY50
2.579
SER51
2.917
VAL85
4.723
TYR87
2.340
THR88
4.045
GLN89
4.326
TRP92
4.328
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| Ligand Name: N-[3-[(5R)-3-azanyl-5-methyl-9,9-bis(oxidanylidene)-2,9$l^{6}-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide | Ligand Info | |||||
| Structure Description | BACE2 xaperone complex with N-{3-[(5R)-3-amino-5-methyl-9,9-dioxo-2,9lambda6-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide | PDB:6JSZ | ||||
| Method | X-ray diffraction | Resolution | 1.53 Å | Mutation | No | [6] |
| PDB Sequence |
ANFLAMVDNL
22 QGGRGYYLEM34 LIGTPPQKLQ44 ILVDTGSSNF54 AVAGTPHSYI64 DTYFDTERSS 74 TYRSKGFDVT84 VKYTQGSWTG94 FVGEDLVTIP104 KGFNTSFLVN114 IATIFESENF 124 FLPGIKWNGI134 LGLAYATLAK144 PSSSLETFFD154 SLVTQANIPN164 VFSMQMCGAG 174 GGSLVLGGIE193 PSLYKGDIWY203 TPIKEEWYYQ213 IEILKLEIGG223 QSLNLDCREY 233 NADKAIVDSG243 TTLLRLPQKV253 FDAVVEAVAR263 ASLIPEFSDG273 FWTGSQLACW 283 WSYFPKISIY299 LRDENSSRSF309 RITILPQLYI319 QPMYECYRFG335 ISPSTNALVI 345 GATVMEGFYV355 IFDRAQKRVG365 FAASPCAEIA375 GAAVSEISGP385 FSTEDVASNC 395 VPA
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .C7O or .C7O2 or .C7O3 or :3C7O;style chemicals stick;color identity;select .A:27 or .A:28 or .A:29 or .A:30 or .A:46 or .A:48 or .A:50 or .A:51 or .A:85 or .A:86 or .A:87 or .A:124 or .A:131 or .A:134 or .A:241 or .A:242 or .A:243 or .A:244 or .A:245 or .A:347; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: 5-(2,2,2-Trifluoro-Ethoxy)-Pyridine-2-Carboxylic Acid [3-((S)-2-Amino-1,4-Dimethyl-6-Oxo-1,4,5,6-Tetrahydro-Pyrimidin-4-Yl)-Phenyl]-Amide | Ligand Info | |||||
| Structure Description | BACE2 FAB INHIBITOR COMPLEX | PDB:3ZKN | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [7] |
| PDB Sequence |
NFLAMVDNLQ
23 GDSGRGYYLE33 MLIGTPPQKL43 QILVDTGSSN53 FAVAGTPHSY63 IDTYFDTERS 73 STYRSKGFDV83 TVKYTQGSWT93 GFVGEDLVTI103 PKGFNTSFLV113 NIATIFESEN 123 FFLPGIKWNG133 ILGLAYATLA143 KPSSSLETFF153 DSLVTQANIP163 NVFSMQMCGA 173 NGGSLVLGGI192 EPSLYKGDIW202 YTPIKEEWYY212 QIEILKLEIG222 GQSLNLDCRE 232 YNADKAIVDS242 GTTLLRLPQK252 VFDAVVEAVA262 RASLIPEFSD272 GFWTGSQLAC 282 WTNSETPWSY292 FPKISIYLRD302 ENSSRSFRIT312 ILPQLYIQPM322 MGAGLNYECY 332 RFGISPSTNA342 LVIGATVMEG352 FYVIFDRAQK362 RVGFAASPCA372 EIAGAAVSEI 382 SGPFSTEDVA392 SNCVP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .WZV or .WZV2 or .WZV3 or :3WZV;style chemicals stick;color identity;select .A:46 or .A:48 or .A:50 or .A:51 or .A:85 or .A:87 or .A:89 or .A:90 or .A:123 or .A:124 or .A:126 or .A:131 or .A:134 or .A:241 or .A:243 or .A:244; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: N-[3-[(9S)-7-azanyl-2,2-bis(fluoranyl)-9-prop-1-ynyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide | Ligand Info | |||||
| Structure Description | BACE2 xaperone complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(prop-1-yn-1-yl)-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide | PDB:7D5U | ||||
| Method | X-ray diffraction | Resolution | 2.04 Å | Mutation | No | [1] |
| PDB Sequence |
FLAMVDNLQG
24 DSGRGYYLEM34 LIGTPPQKLQ44 ILVDTGSSNF54 AVAGTPHSYI64 DTYFDTERSS 74 TYRSKGFDVT84 VKYTQGSWTG94 FVGEDLVTIP104 KGFNTSFLVN114 IATIFESENF 124 FLPGIKWNGI134 LGLAYATLAK144 PSSSLETFFD154 SLVTQANIPN164 VFSMQMCGAN 183 GGSLVLGGIE193 PSLYKGDIWY203 TPIKEEWYYQ213 IEILKLEIGG223 QSLNLDCREY 233 NADKAIVDSG243 TTLLRLPQKV253 FDAVVEAVAR263 ASLIPEFSDG273 FWTGSQLACW 283 TNSETPWSYF293 PKISIYLRDE303 NSSRSFRITI313 LPQLYIQPML327 NYECYRFGIS 337 PSTNALVIGA347 TVMEGFYVIF357 DRAQKRVGFA367 ASPCAEIAGA377 AVSEISGPFS 387 TEDVASNCVP397
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .GX6 or .GX62 or .GX63 or :3GX6;style chemicals stick;color identity;select .A:25 or .A:26 or .A:27 or .A:28 or .A:29 or .A:30 or .A:46 or .A:48 or .A:50 or .A:51 or .A:85 or .A:87 or .A:92 or .A:123 or .A:124 or .A:129 or .A:131 or .A:134 or .A:170 or .A:241 or .A:242 or .A:243 or .A:244 or .A:245 or .A:347; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ASP25
3.769
SER26
3.026
GLY27
3.767
ARG28
4.346
GLY29
3.594
TYR30
3.756
LEU46
3.671
ASP48
2.601
GLY50
3.596
SER51
3.823
VAL85
3.940
TYR87
3.028
TRP92
3.464
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| Ligand Name: 5-Ethoxy-Pyridine-2-Carboxylic Acid [3-((R)-2-Amino-5,5-Difluoro-4-Methyl-5,6-Dihydro-4h-[1,3]oxazin-4-Yl)-4-Fluoro-Phenyl]-Amide | Ligand Info | |||||
| Structure Description | BACE2 XAPERONE COMPLEX | PDB:3ZLQ | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [8] |
| PDB Sequence |
LAMVDNLQGD
25 SGRGYYLEML35 IGTPPQKLQI45 LVDTGSSNFA55 VAGTPHSYID65 TYFDTERSST 75 YRSKGFDVTV85 KYTQGSWTGF95 VGEDLVTIPK105 GFNTSFLVNI115 ATIFESENFF 125 LPGIKWNGIL135 GLAYATLAKP145 SSSLETFFDS155 LVTQANIPNV165 FSMQMCGAGG 184 GSLVLGGIEP194 SLYKGDIWYT204 PIKEEWYYQI214 EILKLEIGGQ224 SLNLDCREYN 234 ADKAIVDSGT244 TLLRLPQKVF254 DAVVEAVARA264 SDGFWTGSQL280 ACWTNSETPW 290 SYFPKISIYL300 RDENSSRSFR310 ITILPQLYIQ320 PMMGAGLNYE330 CYRFGISPST 340 NALVIGATVM350 EGFYVIFDRA360 QKRVGFAASP370 CAEIAGAAVS380 EISGPFSTED 390 VASNCVP
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .6T9 or .6T92 or .6T93 or :36T9;style chemicals stick;color identity;select .A:25 or .A:26 or .A:27 or .A:28 or .A:29 or .A:30 or .A:46 or .A:48 or .A:50 or .A:51 or .A:87 or .A:89 or .A:92 or .A:124 or .A:131 or .A:134 or .A:170 or .A:241 or .A:242 or .A:243 or .A:244 or .A:245 or .A:347; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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ASP25
4.116
SER26
3.397
GLY27
3.542
ARG28
3.701
GLY29
3.130
TYR30
3.705
LEU46
3.453
ASP48
2.581
GLY50
3.870
SER51
3.787
TYR87
3.381
GLN89
4.952
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | 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. | ||||
| REF 2 | Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. J Mol Biol. 2006 Jan 13;355(2):249-61. | ||||
| REF 3 | A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors. ACS Chem Neurosci. 2021 Feb 17;12(4):581-588. | ||||
| REF 4 | JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate. J Med Chem. 2021 Oct 14;64(19):14175-14191. | ||||
| REF 5 | Discovery of Extremely Selective Fused Pyridine-Derived beta-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions. J Med Chem. 2021 Oct 14;64(19):14165-14174. | ||||
| REF 6 | Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2. J Med Chem. 2019 May 23;62(10):5080-5095. | ||||
| REF 7 | Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones. Acta Crystallogr D Biol Crystallogr. 2013 Jun;69(Pt 6):1124-37. | ||||
| REF 8 | beta-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease. J Med Chem. 2013 May 23;56(10):3980-95. | ||||
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