Binding Site Information of Target
| 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 | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Semagacestat | Ligand Info | |||||
| Structure Description | Molecular basis for inhibition of human gamma-secretase by small molecule | PDB:6LR4 | ||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | No | [1] |
| PDB Sequence |
LKYGAKHVIM
84 LFVPVTLCMV94 VVVATIKSVS104 FYTRKDGQLI114 YTPFTEDTET124 VGQRALHSIL 134 NAAIMISVIV144 VMTILLVVLY154 KYRCYKVIHA164 WLIISSLLLL174 FFFSFIYLGE 184 VFKTYNVAVD194 YITVALLIWN204 FGVVGMISIH214 WKGPLRLQQA224 YLIMISALMA 234 LVFIKYLPEW244 TAWLILAVIS254 VYDLVAVLCP264 KGPLRMLVET274 AQERNETLFP 284 ALIYSSTRGV379 KLGLGDFIFY389 SVLVGKASAT399 ASGDWNTTIA409 CFVAILIGLC 419 LTLLLLAIFK429 KALPALPISI439 TFGLVFYFAT449 DYLVQPFMDQ459 LAFHQFYI |
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|
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TYR77
4.363
ASP257
4.984
VAL261
4.865
LEU268
4.750
VAL272
4.147
GLN276
4.238
LEU282
3.871
ILE287
4.137
GLY378
4.644
VAL379
3.611
LYS380
3.229
|
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| Ligand Name: BMS-708163 | Ligand Info | |||||
| Structure Description | Human gamma-secretase in complex with small molecule Avagacestat | PDB:6LQG | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [1] |
| PDB Sequence |
LKYGAKHVIM
84 LFVPVTLCMV94 VVVATIKSVS104 FYTRKDGQLI114 YTPFTEDTET124 VGQRALHSIL 134 NAAIMISVIV144 VMTILLVVLY154 KYRCYKVIHA164 WLIISSLLLL174 FFFSFIYLGE 184 VFKTYNVAVD194 YITVALLIWN204 FGVVGMISIH214 WKGPLRLQQA224 YLIMISALMA 234 LVFIKYLPEW244 TAWLILAVIS254 VYDLVAVLCP264 KGPLRMLVET274 AQERNETLFP 284 ALIYSSTERG378 VKLGLGDFIF388 YSVLVGKASA398 TASGDWNTTI408 ACFVAILIGL 418 CLTLLLLAIF428 KKALPALPIS438 ITFGLVFYFA448 TDYLVQPFMD458 QLAFHQFYI |
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|
|
LEU85
4.484
VAL261
3.804
LEU268
3.248
VAL272
3.262
ALA275
4.489
GLN276
3.540
GLU280
4.454
LEU282
4.360
VAL379
4.514
LYS380
3.164
LEU381
3.597
|
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| Ligand Name: phosphatidylethanolamine | Ligand Info | |||||
| Structure Description | CryoEM structure of human gamma-secretase in complex with E2012 and L685458 | PDB:7D8X | ||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | No | [1] |
| PDB Sequence |
KYGAKHVIML
85 FVPVTLCMVV95 VVATIKSVSF105 YTRKDGQLIY115 TPFTEDTETV125 GQRALHSILN 135 AAIMISVIVV145 MTILLVVLYK155 YRCYKVIHAW165 LIISSLLLLF175 FFSFIYLGEV 185 FKTYNVAVDY195 ITVALLIWNF205 GVVGMISIHW215 KGPLRLQQAY225 LIMISALMAL 235 VFIKYLPEWT245 AWLILAVISV255 YDLVAVLCPK265 GPLRMLVETA275 QERNETLFPA 285 LIYSSTRGVK380 LGLGDFIFYS390 VLVGKASATA400 SGDWNTTIAC410 FVAILIGLCL 420 TLLLLAIFKK430 ALPALPISIT440 FGLVFYFATD450 YLVQPFMDQL460 AFHQFYI |
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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 .PTY or .PTY2 or .PTY3 or :3PTY;style chemicals stick;color identity;select .B:128 or .B:244 or .B:247 or .B:248 or .B:251 or .B:252 or .B:254 or .B:255 or .B:436 or .B:440 or .B:443 or .B:444 or .B:447 or .B:451; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| Ligand Name: 1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one | Ligand Info | |||||
| Structure Description | CryoEM structure of human gamma-secretase in complex with E2012 and L685458 | PDB:7D8X | ||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | No | [1] |
| PDB Sequence |
KYGAKHVIML
85 FVPVTLCMVV95 VVATIKSVSF105 YTRKDGQLIY115 TPFTEDTETV125 GQRALHSILN 135 AAIMISVIVV145 MTILLVVLYK155 YRCYKVIHAW165 LIISSLLLLF175 FFSFIYLGEV 185 FKTYNVAVDY195 ITVALLIWNF205 GVVGMISIHW215 KGPLRLQQAY225 LIMISALMAL 235 VFIKYLPEWT245 AWLILAVISV255 YDLVAVLCPK265 GPLRMLVETA275 QERNETLFPA 285 LIYSSTRGVK380 LGLGDFIFYS390 VLVGKASATA400 SGDWNTTIAC410 FVAILIGLCL 420 TLLLLAIFKK430 ALPALPISIT440 FGLVFYFATD450 YLVQPFMDQL460 AFHQFYI |
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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 .GZR or .GZR2 or .GZR3 or :3GZR;style chemicals stick;color identity;select .B:105 or .B:106 or .B:176 or .B:177 or .B:180 or .B:181 or .B:232 or .B:236 or .B:240; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| Ligand Name: l-685,458 | Ligand Info | |||||
| Structure Description | CryoEM structure of human gamma-secretase in complex with E2012 and L685458 | PDB:7D8X | ||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | No | [1] |
| PDB Sequence |
KYGAKHVIML
85 FVPVTLCMVV95 VVATIKSVSF105 YTRKDGQLIY115 TPFTEDTETV125 GQRALHSILN 135 AAIMISVIVV145 MTILLVVLYK155 YRCYKVIHAW165 LIISSLLLLF175 FFSFIYLGEV 185 FKTYNVAVDY195 ITVALLIWNF205 GVVGMISIHW215 KGPLRLQQAY225 LIMISALMAL 235 VFIKYLPEWT245 AWLILAVISV255 YDLVAVLCPK265 GPLRMLVETA275 QERNETLFPA 285 LIYSSTRGVK380 LGLGDFIFYS390 VLVGKASATA400 SGDWNTTIAC410 FVAILIGLCL 420 TLLLLAIFKK430 ALPALPISIT440 FGLVFYFATD450 YLVQPFMDQL460 AFHQFYI |
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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 .FTO or .FTO2 or .FTO3 or :3FTO;style chemicals stick;color identity;select .B:77 or .B:85 or .B:143 or .B:253 or .B:256 or .B:257 or .B:261 or .B:268 or .B:271 or .B:272 or .B:276 or .B:282 or .B:286 or .B:287 or .B:378 or .B:379 or .B:380 or .B:381 or .B:382 or .B:383 or .B:384 or .B:385 or .B:388 or .B:421 or .B:422 or .B:425 or .B:430 or .B:431 or .B:432 or .B:433 or .B:434 or .B:435; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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
|
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: ~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide | Ligand Info | |||||
| Structure Description | CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560 | PDB:7Y5T | ||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [2] |
| PDB Sequence |
LKYGAKHVIM
84 LFVPVTLCMV94 VVVATIKSVS104 FYTRKDGQLI114 YTPFTEDTET124 VGQRALHSIL 134 NAAIMISVIV144 VMTILLVVLY154 KYRCYKVIHA164 WLIISSLLLL174 FFFSFIYLGE 184 VFKTYNVAVD194 YITVALLIWN204 FGVVGMISIH214 WKGPLRLQQA224 YLIMISALMA 234 LVFIKYLPEW244 TAWLILAVIS254 VYDLVAVLCP264 KGPLRMLVET274 AQERNETLFP 284 ALIYSSTRGV379 KLGLGDFIFY389 SVLVGKASAT399 ASGDWNTTIA409 CFVAILIGLC 419 LTLLLLAIFK429 KALPALPISI439 TFGLVFYFAT449 DYLVQPFMDQ459 LAFHQFYI |
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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 .IGD or .IGD2 or .IGD3 or :3IGD;style chemicals stick;color identity;select .B:85 or .B:257 or .B:261 or .B:272 or .B:275 or .B:276 or .B:280 or .B:281 or .B:282 or .B:287 or .B:379 or .B:380 or .B:381 or .B:382 or .B:385 or .B:418 or .B:421 or .B:422 or .B:425 or .B:431 or .B:432 or .B:433 or .B:434; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU85
4.113
ASP257
4.851
VAL261
4.198
VAL272
3.763
ALA275
4.011
GLN276
3.542
GLU280
3.357
THR281
3.464
LEU282
3.332
ILE287
4.300
VAL379
3.777
LYS380
3.252
|
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| 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. | ||||
| REF 2 | Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. | ||||
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