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 T93105 Target Info
Target Name Presenilin 1 (PSEN1)
Synonyms S182 protein; Protein S182; Presenilin-1; PSNL1; PS1; PS-1; AD3
Target Type Clinical trial Target
Gene Name PSEN1
Biochemical Class Peptidase
UniProt ID
PSN1_HUMAN
Ligand General Information  Top
Ligand Name l-685,458 Ligand Info
Canonical SMILES CC(C)CC(C(=O)NC(CC1=CC=CC=C1)C(=O)N)NC(=O)C(CC2=CC=CC=C2)CC(C(CC3=CC=CC=C3)NC(=O)OC(C)(C)C)O
InChI 1S/C39H52N4O6/c1-26(2)21-33(37(47)41-32(35(40)45)24-29-19-13-8-14-20-29)42-36(46)30(22-27-15-9-6-10-16-27)25-34(44)31(23-28-17-11-7-12-18-28)43-38(48)49-39(3,4)5/h6-20,26,30-34,44H,21-25H2,1-5H3,(H2,40,45)(H,41,47)(H,42,46)(H,43,48)/t30-,31+,32+,33+,34-/m1/s1
InChIKey MURCDOXDAHPNRQ-ZJKZPDEISA-N
PubChem Compound ID 5479543
Drug Binding Sites of Target  Top
PDB ID: 7D8X      CryoEM structure of human gamma-secretase in complex with E2012 and L685458
Method Electron microscopy Resolution 2.60 Å Mutation No [1]
PDB Sequence
KYGAKHVIML
85
FVPVTLCMVV
95
VVATIKSVSF
105
YTRKDGQLIY
115
TPFTEDTETV
125

GQRALHSILN
135
AAIMISVIVV
145
MTILLVVLYK
155
YRCYKVIHAW
165
LIISSLLLLF
175

FFSFIYLGEV
185
FKTYNVAVDY
195
ITVALLIWNF
205
GVVGMISIHW
215
KGPLRLQQAY
225

LIMISALMAL
235
VFIKYLPEWT
245
AWLILAVISV
255
YDLVAVLCPK
265
GPLRMLVETA
275

QERNETLFPA
285
LIYSSTRGVK
380
LGLGDFIFYS
390
VLVGKASATA
400
SGDWNTTIAC
410

FVAILIGLCL
420
TLLLLAIFKK
430
ALPALPISIT
440
FGLVFYFATD
450
YLVQPFMDQL
460

AFHQFYI
Residue
Distance (Å)
TYR77
3.775
LEU85
3.757
ILE143
4.012
ILE253
4.111
TYR256
4.520
ASP257
2.634
VAL261
4.185
LEU268
3.859
LEU271
3.865
VAL272
3.623
GLN276
4.733
LEU282
4.088
LEU286
3.450
ILE287
3.873
GLY378
4.798
VAL379
3.934
Residue
Distance (Å)
LYS380
3.253
LEU381
3.740
GLY382
3.309
LEU383
3.819
GLY384
3.222
ASP385
3.316
PHE388
4.052
THR421
3.807
LEU422
4.071
LEU425
3.765
LYS430
4.041
ALA431
3.677
LEU432
2.760
PRO433
4.214
ALA434
3.777
LEU435
3.905
PDB ID: 7C9I      Human gamma-secretase in complex with small molecule L-685,458
Method Electron microscopy Resolution 3.10 Å Mutation No [1]
PDB Sequence
KYGAKHVIML
85
FVPVTLCMVV
95
VVATIKSVSF
105
YTRKDGQLIY
115
TPFTEDTETV
125

GQRALHSILN
135
AAIMISVIVV
145
MTILLVVLYK
155
YRCYKVIHAW
165
LIISSLLLLF
175

FFSFIYLGEV
185
FKTYNVAVDY
195
ITVALLIWNF
205
GVVGMISIHW
215
KGPLRLQQAY
225

LIMISALMAL
235
VFIKYLPEWT
245
AWLILAVISV
255
YDLVAVLCPK
265
GPLRMLVETA
275

QERNETLFPA
285
LIYSSTRGVK
380
LGLGDFIFYS
390
VLVGKASATA
400
SGDWNTTIAC
410

FVAILIGLCL
420
TLLLLAIFKK
430
ALPALPISIT
440
FGLVFYFATD
450
YLVQPFMDQL
460

AFHQFYI
Residue
Distance (Å)
TYR77
4.738
LEU85
4.969
ILE143
4.248
THR147
4.674
ILE253
4.721
ASP257
2.940
VAL261
4.131
LEU268
3.948
LEU271
4.415
VAL272
3.685
GLN276
4.826
LEU282
4.948
LEU286
2.484
ILE287
4.254
VAL379
3.734
LYS380
2.990
Residue
Distance (Å)
LEU381
3.511
GLY382
3.132
LEU383
3.940
GLY384
3.377
ASP385
2.712
PHE388
3.049
LEU418
4.855
THR421
3.439
LEU425
2.941
LYS430
4.236
ALA431
4.057
LEU432
3.227
PRO433
4.449
ALA434
3.248
LEU435
3.083
References  Top
REF 1 Structural basis of Gamma-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14.

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