Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T79031 | Target Info | |||
| Target Name | Beta-secretase 1 (BACE1) | ||||
| 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 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | BACE1 | ||||
| Biochemical Class | Peptidase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Urea | Ligand Info | |||
| Canonical SMILES | C(=O)(N)N | ||||
| InChI | 1S/CH4N2O/c2-1(3)4/h(H4,2,3,4) | ||||
| InChIKey | XSQUKJJJFZCRTK-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 1176 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5V0N BACE1 in complex with inhibitor 5g | ||||||
| Method | X-ray diffraction | Resolution | 2.15 Å | Mutation | No | [1] |
| PDB Sequence |
FVEMVDNLRG
8 KSGQGYYVEM18 TVGSPPQTLN28 ILVDTGSSNF38 AVGAAPHPFL48 HRYYQRQLSS 58 TYRDLRKGVY68 VPYTQGKWEG78 ELGTDLVSIP88 HGPNVTVRAN98 IAAITESDKF 108 FINGSNWEGI118 LGLAYAEIAR128 PDDSLEPFFD138 SLVKQTHVPN148 LFSLQLCGAG 158 ASVGGSMIIG177 GIDHSLYTGS187 LWYTPIRREW197 YYEVIIVRVE207 INGQDLKMDC 217 KEYNYDKSIV227 DSGTTNLRLP237 KKVFEAAVKS247 IKAASSTEKF257 PDGFWLGEQL 267 VCWQAGTTPW277 NIFPVISLYL287 MGEVTNQSFR297 ITILPQQYLR307 PVDDCYKFAI 324 SQSSTGTVMG334 AVIMEGFYVV344 FDRARKRIGF354 AVSACHVHDE364 FRTAAVEGPF 374 VTLDMEDCGY384 N
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| PDB ID: 6DHC X-ray structure of BACE1 in complex with a bicyclic isoxazoline carboxamide as the P3 ligand | ||||||
| Method | X-ray diffraction | Resolution | 2.85 Å | Mutation | No | [2] |
| PDB Sequence |
GSFVEMVDNL
6 RGKSGQGYYV16 EMTVGSPPQT26 LNILVDTGSS36 NFAVGAAPHP46 FLHRYYQRQL 56 SSTYRDLRKG66 VYVPYTQGKW76 EGELGTDLVS86 IPHGPNVTVR96 ANIAAITESD 106 KFFINGSNWE116 GILGLAYAEI126 ARPDDSLEPF136 FDSLVKQTHV146 PNLFSLQLCG 156 ASVGGSMIIG177 GIDHSLYTGS187 LWYTPIRREW197 YYEVIIVRVE207 INGQDLKMDC 217 KEYNYDKSIV227 DSGTTNLRLP237 KKVFEAAVKS247 IKAASSTEKF257 PDGFWLGEQL 267 VCWQAGTTPW277 NIFPVISLYL287 MGEVTNQSFR297 ITILPQQYLR307 PVEDVATSQD 317 DCYKFAISQS327 STGTVMGAVI337 MEGFYVVFDR347 ARKRIGFAVS357 ACHVHDEFRT 367 AAVEGPFVTL377 DMEDCGYN
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| PDB ID: 4FGX Crystal structure of bace1 with novel inhibitor | ||||||
| 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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| PDB ID: 3TPP Crystal structure of BACE1 complexed with an inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [4] |
| PDB Sequence |
RGSFVEMVDN
5 LRGKSGQGYY15 VEMTVGSPPQ25 TLNILVDTGS35 SNFAVGAAPH45 PFLHRYYQRQ 55 LSSTYRDLRK65 GVYVPYTQGA75 WAGELGTDLV85 SIPHGPNVTV95 RANIAAITES 105 DKFFINGSNW115 EGILGLAYAE125 IARPDDSLEP135 FFDSLVKQTH145 VPNLFSLQLC 155 GAVGGSMIIG177 GIDHSLYTGS187 LWYTPIRREW197 YYEVIIVRVE207 INGQDLKMDC 217 KEYNYDKSIV227 DSGTTNLRLP237 KKVFEAAVKS247 IKAASSTEKF257 PDGFWLGEQL 267 VCWQAGTTPW277 NIFPVISLYL287 MGEVTNQSFR297 ITILPQQYLR307 PVETSQDDCY 320 KFAISQSSTG330 TVMGAVIMEG340 FYVVFDRARK350 RIGFAVSACH360 VHDEFRTAAV 370 EGPFVTLDME380 DCGYN
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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 .URE or .URE2 or .URE3 or :3URE;style chemicals stick;color identity;select .A:-1 or .A:17 or .A:19 or .A:26 or .A:27 or .A:28 or .A:45 or .A:47 or .A:49 or .A:50 or .A:65 or .A:66 or .A:67 or .A:68 or .A:69 or .A:84 or .A:88 or .A:89 or .A:94 or .A:95 or .A:96 or .A:105 or .A:106 or .A:107 or .A:108 or .A:109 or .A:114 or .A:116 or .A:128 or .A:129 or .A:143 or .A:147 or .A:176 or .A:177 or .A:178 or .A:208 or .A:209 or .A:211 or .A:213 or .A:214 or .A:215 or .A:242 or .A:243 or .A:247 or .A:250 or .A:251 or .A:252 or .A:278 or .A:279 or .A:280 or .A:281 or .A:288 or .A:291 or .A:292 or .A:293 or .A:294 or .A:366 or .A:376 or .A:377 or .A:378 or .A:379 or .A:380; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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PHE-1
3.557
GLU17
4.252
THR19
4.338
THR26
3.091
LEU27
3.892
ASN28
3.645
HIS45
3.051
PHE47
3.656
HIS49
3.510
ARG50
3.585
LYS65
4.907
GLY66
4.480
VAL67
3.695
TYR68
2.666
VAL69
4.981
LEU84
3.620
PRO88
3.576
HIS89
4.807
THR94
3.085
VAL95
3.867
ARG96
3.208
SER105
2.704
ASP106
3.861
LYS107
3.557
PHE108
2.907
PHE109
2.997
ASN114
4.810
GLU116
2.686
ARG128
3.362
PRO129
3.608
GLN143
2.981
PRO147
3.439
ILE176
4.728
GLY177
3.121
GLY178
4.874
ILE208
2.866
ASN209
2.937
GLN211
3.259
LEU213
2.966
LYS214
3.650
MET215
3.574
GLU242
4.718
ALA243
3.853
SER247
3.014
ALA250
3.697
ALA251
3.132
SER252
4.549
ASN278
3.222
ILE279
2.681
PHE280
3.430
PRO281
3.731
MET288
4.897
VAL291
4.463
THR292
3.493
ASN293
2.854
GLN294
4.861
ARG366
3.391
THR376
4.062
LEU377
4.284
ASP378
3.620
MET379
3.164
GLU380
2.964
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| PDB ID: 3TPJ APO structure of BACE1 | ||||||
| Method | X-ray diffraction | Resolution | 1.61 Å | Mutation | Yes | [4] |
| PDB Sequence |
RGSFVEMVDN
5 LRGKSGQGYY15 VEMTVGSPPQ25 TLNILVDTGS35 SNFAVGAAPH45 PFLHRYYQRQ 55 LSSTYRDLRK65 GVYVPYTQGA75 WAGELGTDLV85 SIPHGPNVTV95 RANIAAITES 105 DKFFINGSNW115 EGILGLAYAE125 IARPDDSLEP135 FFDSLVKQTH145 VPNLFSLQLC 155 GASVGGSMII176 GGIDHSLYTG186 SLWYTPIRRE196 WYYEVIIVRV206 EINGQDLKMD 216 CKEYNYDKSI226 VDSGTTNLRL236 PKKVFEAAVK246 SIKAASSTEK256 FPDGFWLGEQ 266 LVCWQAGTTP276 WNIFPVISLY286 LMGEVTNQSF296 RITILPQQYL306 RPVETSQDDC 319 YKFAISQSST329 GTVMGAVIME339 GFYVVFDRAR349 KRIGFAVSAC359 HVHDEFRTAA 369 VEGPFVTLDM379 EDCGYNI
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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 .URE or .URE2 or .URE3 or :3URE;style chemicals stick;color identity;select .A:-1 or .A:1 or .A:60 or .A:61 or .A:62 or .A:66 or .A:67 or .A:68 or .A:69 or .A:88 or .A:89 or .A:128 or .A:129 or .A:145 or .A:147 or .A:176 or .A:177 or .A:178; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 3UQU Crystal structure of BACE1 with its inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [5] |
| PDB Sequence |
RGSFVEMVDN
5 LRGKSGQGYY15 VEMTVGSPPQ25 TLNILVDTGS35 SNFAVGAAPH45 PFLHRYYQRQ 55 LSSTYRDLRK65 GVYVPYTQGA75 WAGELGTDLV85 SIPHGPNVTV95 RANIAAITES 105 DKFFINGSNW115 EGILGLAYAE125 IARPDDSLEP135 FFDSLVKQTH145 VPNLFSLQLC 155 GAVGGSMIIG177 GIDHSLYTGS187 LWYTPIRREW197 YYEVIIVRVE207 INGQDLKMDC 217 KEYNYDKSIV227 DSGTTNLRLP237 KKVFEAAVKS247 IKAASSTEKF257 PDGFWLGEQL 267 VCWQAGTTPW277 NIFPVISLYL287 MGEVTNQSFR297 ITILPQQYLR307 PVESQDDCYK 321 FAISQSSTGT331 VMGAVIMEGF341 YVVFDRARKR351 IGFAVSACHV361 HDEFRTAAVE 371 GPFVTLDMED381 CGYN
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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 .URE or .URE2 or .URE3 or :3URE;style chemicals stick;color identity;select .A:62 or .A:64 or .A:242; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 3UQX Crystal structure of BACE1 with its inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [6] |
| PDB Sequence |
RGSFVEMVDN
5 LRGKSGQGYY15 VEMTVGSPPQ25 TLNILVDTGS35 SNFAVGAAPH45 PFLHRYYQRQ 55 LSSTYRDLRK65 GVYVPYTQGA75 WAGELGTDLV85 SIPHGPNVTV95 RANIAAITES 105 DKFFINGSNW115 EGILGLAYAE125 IARPDDSLEP135 FFDSLVKQTH145 VPNLFSLQLC 155 GAVGGSMIIG177 GIDHSLYTGS187 LWYTPIRREW197 YYEVIIVRVE207 INGQDLKMDC 217 KEYNYDKSIV227 DSGTTNLRLP237 KKVFEAAVKS247 IKAASSTEKF257 PDGFWLGEQL 267 VCWQAGTTPW277 NIFPVISLYL287 MGEVTNQSFR297 ITILPQQYLR307 PVESQDDCYK 321 FAISQSSTGT331 VMGAVIMEGF341 YVVFDRARKR351 IGFAVSACHV361 HDEFRTAAVE 371 GPFVTLDMED381 CGYNI
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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 .URE or .URE2 or .URE3 or :3URE;style chemicals stick;color identity;select .A:22 or .A:23 or .A:47 or .A:58 or .A:60 or .A:61 or .A:62 or .A:64 or .A:66 or .A:67 or .A:68 or .A:69 or .A:72 or .A:107 or .A:109 or .A:128 or .A:129 or .A:198 or .A:224 or .A:226 or .A:233 or .A:235 or .A:325 or .A:326 or .A:329 or .A:332; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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SER22
2.876
PRO23
3.885
PHE47
3.826
SER58
2.786
TYR60
4.482
ARG61
3.595
ASP62
2.993
ARG64
3.623
GLY66
4.389
VAL67
3.594
TYR68
2.564
VAL69
4.806
THR72
4.275
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| PDB ID: 4FCO Crystal structure of bace1 with its inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.76 Å | Mutation | Yes | [7] |
| PDB Sequence |
GSFVEMVDNL
54 RGKSGQGYYV64 EMTVGSPPQT74 LNILVDTGSS84 NFAVGAAPHP94 FLHRYYQRQL 104 SSTYRDLRKG114 VYVPYTQGAW124 AGELGTDLVS134 IPHGPNVTVR144 ANIAAITESD 154 KFFINGSNWE164 GILGLAYAEI174 ARPDDSLEPF184 FDSLVKQTHV194 PNLFSLQLCG 204 AVGGSMIIGG226 IDHSLYTGSL236 WYTPIRREWY246 YEVIIVRVEI256 NGQDLKMDCK 266 EYNYDKSIVD276 SGTTNLRLPK286 KVFEAAVKSI296 KAASSTEKFP306 DGFWLGEQLV 316 CWQAGTTPWN326 IFPVISLYLM336 GEVTNQSFRI346 TILPQQYLRP356 VETSQDDCYK 369 FAISQSSTGT379 VMGAVIMEGF389 YVVFDRARKR399 IGFAVSACHV409 HDEFRTAAVE 419 GPFVTLDMED429 CGYN
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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 .URE or .URE2 or .URE3 or :3URE;style chemicals stick;color identity;select .A:95 or .A:155 or .A:157 or .A:281 or .A:283 or .A:373 or .A:374; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1'-P2' ligands. Bioorg Med Chem Lett. 2017 Jun 1;27(11):2432-2438. | ||||
| REF 2 | Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. Bioorg Med Chem Lett. 2018 Aug 15;28(15):2605-2610. | ||||
| 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 | Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Acta Crystallogr D Biol Crystallogr. 2012 Jan;68(Pt 1):13-25. | ||||
| REF 5 | Flexibility of the Flap in the Active Site of BACE1 as Revealed by Crystal Structures and MD simulations | ||||
| REF 6 | Flexibility of the Flap in the Active Site of BACE1 as Revealed by Crystal Structures and MD simulations | ||||
| REF 7 | Flexibility of the Flap in the Active Site of BACE1 as Revealed by Crystal Structures and MD simulations | ||||
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