Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
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
BACE1_HUMAN
Ligand General Information  Top
Ligand Name N-[(1S,2R)-1-Benzyl-3-(cyclopropylamino)-2-hydroxypropyl]-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]isophthalamide Ligand Info
Canonical SMILES CC(C1=CC=CC=C1)NC(=O)C2=CC(=CC(=C2)N(C)S(=O)(=O)C)C(=O)NC(CC3=CC=CC=C3)C(CNC4CC4)O
InChI 1S/C31H38N4O5S/c1-21(23-12-8-5-9-13-23)33-30(37)24-17-25(19-27(18-24)35(2)41(3,39)40)31(38)34-28(16-22-10-6-4-7-11-22)29(36)20-32-26-14-15-26/h4-13,17-19,21,26,28-29,32,36H,14-16,20H2,1-3H3,(H,33,37)(H,34,38)/t21-,28+,29-/m1/s1
InChIKey VPNIQGRFZCTBEZ-SPTGULJVSA-N
PubChem Compound ID 5287532
Drug Binding Sites of Target  Top
PDB ID: 3TPP      Crystal structure of BACE1 complexed with an inhibitor
Method X-ray diffraction Resolution 1.60 Å Mutation Yes [1]
PDB Sequence
RGSFVEMVDN
5
LRGKSGQGYY
15
VEMTVGSPPQ
25
TLNILVDTGS
35
SNFAVGAAPH
45

PFLHRYYQRQ
55
LSSTYRDLRK
65
GVYVPYTQGA
75
WAGELGTDLV
85
SIPHGPNVTV
95

RANIAAITES
105
DKFFINGSNW
115
EGILGLAYAE
125
IARPDDSLEP
135
FFDSLVKQTH
145

VPNLFSLQLC
155
GAVGGSMIIG
177
GIDHSLYTGS
187
LWYTPIRREW
197
YYEVIIVRVE
207

INGQDLKMDC
217
KEYNYDKSIV
227
DSGTTNLRLP
237
KKVFEAAVKS
247
IKAASSTEKF
257

PDGFWLGEQL
267
VCWQAGTTPW
277
NIFPVISLYL
287
MGEVTNQSFR
297
ITILPQQYLR
307

PVETSQDDCY
320
KFAISQSSTG
330
TVMGAVIMEG
340
FYVVFDRARK
350
RIGFAVSACH
360

VHDEFRTAAV
370
EGPFVTLDME
380
DCGYN
Residue
Distance (Å)
GLY11
3.358
GLN12
3.505
GLY13
3.360
TYR14
4.051
LEU30
3.336
ASP32
2.699
GLY34
3.136
SER35
3.534
TYR71
3.528
THR72
3.214
GLN73
3.068
PHE108
3.641
ILE110
3.997
TRP115
3.573
ILE118
3.880
Residue
Distance (Å)
TYR198
3.411
ILE226
3.214
ASP228
2.662
SER229
3.416
GLY230
3.056
THR231
3.594
THR232
3.064
ASN233
3.038
ARG235
3.213
ARG307
3.616
SER325
3.443
VAL332
4.254
ALA335
3.539
GLU339
4.999
PDB ID: 3TPR      Crystal structure of BACE1 complexed with an inhibitor
Method X-ray diffraction Resolution 2.55 Å Mutation No [1]
PDB Sequence
FVEMVDNLRG
8
KSGQGYYVEM
18
TVGSPPQTLN
28
ILVDTGSSNF
38
AVGAAPHPFL
48

HRYYQRQLSS
58
TYRDLRKGVY
68
VPYTQGKWEG
78
ELGTDLVSIP
88
HGPNVTVRAN
98

IAAITESDKF
108
FINGSNWEGI
118
LGLAYAEIAR
128
PDDSLEPFFD
138
SLVKQTHVPN
148

LFSLQLCGAA
168
SVGGSMIIGG
178
IDHSLYTGSL
188
WYTPIRREWY
198
YEVIIVRVEI
208

NGQDLKMDCK
218
EYNYDKSIVD
228
SGTTNLRLPK
238
KVFEAAVKSI
248
KAASSTEKFP
258

DGFWLGEQLV
268
CWQAGTTPWN
278
IFPVISLYLM
288
GEVTNQSFRI
298
TILPQQYLRP
308

VDDCYKFAIS
325
QSSTGTVMGA
335
VIMEGFYVVF
345
DRARKRIGFA
355
VSACHVHDEF
365

RTAAVEGPFV
375
TLDMEDCGYN
385
I
Residue
Distance (Å)
GLY11
3.577
GLN12
3.762
GLY13
3.237
TYR14
3.832
LEU30
3.726
ASP32
2.669
GLY34
3.137
SER35
3.441
TYR71
3.904
THR72
3.961
PHE108
3.856
ILE110
4.371
TRP115
4.202
Residue
Distance (Å)
ILE118
3.723
TYR198
3.396
ILE226
3.834
ASP228
2.919
SER229
3.070
GLY230
2.858
THR231
3.663
THR232
2.431
ASN233
2.940
ARG235
2.880
ARG307
4.874
SER325
3.818
ALA335
3.854
PDB ID: 2B8L      Crystal structure of human beta secretase complexed with inhibitor
Method X-ray diffraction Resolution 1.70 Å Mutation Yes [2]
PDB Sequence
RRGSFVEMVD
4
NLRGKSGQGY
14
YVEMTVGSPP
24
QTLNILVDTG
34
SSNFAVGAAP
44

HPFLHRYYQR
54
QLSSTYRDLR
64
KGVYVPYTQG
74
AWAGELGTDL
84
VSIPHGPNVT
94

VRANIAAITE
104
SDKFFINGSN
114
WEGILGLAYA
124
EIARPDDSLE
134
PFFDSLVKQT
144

HVPNLFSLQL
154
CGAVGGSMII
176
GGIDHSLYTG
186
SLWYTPIRRE
196
WYYEVIIVRV
206

EINGQDLKMD
216
CKEYNYDKSI
226
VDSGTTNLRL
236
PKKVFEAAVK
246
SIKAASSTEK
256

FPDGFWLGEQ
266
LVCWQAGTTP
276
WNIFPVISLY
286
LMGEVTNQSF
296
RITILPQQYL
306

RPVEDVATSQ
316
DDCYKFAISQ
326
SSTGTVMGAV
336
IMEGFYVVFD
346
RARKRIGFAV
356

SACHVHDEFR
366
TAAVEGPFVT
376
LDMEDCGYN
Residue
Distance (Å)
GLY11
3.372
GLN12
3.453
GLY13
3.267
TYR14
3.941
LEU30
3.239
ASP32
2.659
GLY34
3.071
SER35
3.622
TYR71
3.514
THR72
3.188
GLN73
3.071
LYS107
4.988
PHE108
3.502
ILE110
3.942
TRP115
3.662
ILE118
3.858
Residue
Distance (Å)
TYR198
3.503
ILE226
3.364
ASP228
2.672
SER229
3.458
GLY230
2.992
THR231
3.640
THR232
3.084
ASN233
2.979
ARG235
3.310
ARG307
3.743
LYS321
4.546
SER325
3.406
VAL332
4.300
ALA335
3.614
GLU339
4.847
References  Top
REF 1 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 2 Conformationally biased P3 amide replacements of beta-secretase inhibitors. Bioorg Med Chem Lett. 2006 Feb;16(3):641-4.

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