Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T99840 | Target Info | |||
| Target Name | Gamma-secretase (GS) | ||||
| Synonyms | Presenilin-stabilization factor-like; PSFL; Aph-1beta | ||||
| Target Type | Successful Target | ||||
| Gene Name | APH1A; APH1B; NCSTN; PSENEN; PSEN1 | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Cholesterol | Ligand Info | |||
| Canonical SMILES | CC(C)CCCC(C)C1CCC2C1(CCC3C2CC=C4C3(CCC(C4)O)C)C | ||||
| InChI | 1S/C27H46O/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28)13-15-26(20,4)25(22)14-16-27(23,24)5/h9,18-19,21-25,28H,6-8,10-17H2,1-5H3/t19-,21+,22+,23-,24+,25+,26+,27-/m1/s1 | ||||
| InChIKey | HVYWMOMLDIMFJA-DPAQBDIFSA-N | ||||
| PubChem Compound ID | 5997 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 6IYC Recognition of the Amyloid Precursor Protein by Human gamma-secretase | ||||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | Yes | [1] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
|
ARG66
3.518
TYR69
3.350
ILE73
4.010
SER153
4.583
TYR155
3.554
THR159
4.240
PHE162
3.867
ARG186
4.260
TRP188
3.996
LEU192
3.698
LEU199
4.360
GLY202
3.240
|
|||||
| PDB ID: 7D8X CryoEM structure of human gamma-secretase in complex with E2012 and L685458 | ||||||
| Method | Electron microscopy | Resolution | 2.60 Å | Mutation | No | [2] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
|
TYR69
4.003
ILE73
3.713
TYR155
4.278
THR159
3.766
PHE162
3.541
ARG184
4.789
ARG186
4.526
TRP188
3.591
LEU192
3.669
LEU199
3.810
GLY202
3.242
LEU203
4.278
|
|||||
| PDB ID: 6IDF Cryo-EM structure of gamma secretase in complex with a Notch fragment | ||||||
| Method | Electron microscopy | Resolution | 2.70 Å | Mutation | Yes | [3] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
|
ARG66
4.135
TYR69
3.791
ILE73
3.704
TYR155
3.636
THR159
4.040
PHE162
3.330
ARG186
4.801
TRP188
3.608
LEU192
3.665
SER196
4.791
LEU198
4.519
LEU199
3.852
|
|||||
| PDB ID: 7Y5T CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560 | ||||||
| Method | Electron microscopy | Resolution | 2.90 Å | Mutation | No | [4] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:69 or .C:73 or .C:153 or .C:155 or .C:159 or .C:162 or .C:188 or .C:192 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:223 or .C:226 or .C:227 or .C:230; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR69
3.768
ILE73
3.741
SER153
4.152
TYR155
3.845
THR159
4.437
PHE162
4.397
TRP188
4.983
LEU192
3.948
LEU199
4.807
GLY202
3.240
LEU203
4.263
|
|||||
| PDB ID: 6LR4 Molecular basis for inhibition of human gamma-secretase by small molecule | ||||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | No | [2] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:69 or .C:73 or .C:155 or .C:158 or .C:159 or .C:162 or .C:184 or .C:188 or .C:192 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:223 or .C:224 or .C:227 or .C:230; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR69
3.743
ILE73
3.822
TYR155
3.928
LEU158
4.802
THR159
4.141
PHE162
4.411
ARG184
4.244
TRP188
3.733
LEU192
3.767
LEU199
3.848
GLY202
3.498
|
|||||
| PDB ID: 7Y5X CryoEM structure of PS2-containing gamma-secretase treated with MRK-560 | ||||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | No | [4] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:69 or .C:73 or .C:153 or .C:155 or .C:158 or .C:159 or .C:162 or .C:186 or .C:188 or .C:192 or .C:196 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:220 or .C:223 or .C:224 or .C:227 or .C:230; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR69
3.430
ILE73
3.790
SER153
4.647
TYR155
3.633
LEU158
4.576
THR159
3.771
PHE162
4.356
ARG186
4.640
TRP188
3.599
LEU192
4.145
SER196
3.836
LEU199
4.809
GLY202
3.282
|
|||||
| PDB ID: 6LQG Human gamma-secretase in complex with small molecule Avagacestat | ||||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [2] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:69 or .C:73 or .C:153 or .C:155 or .C:159 or .C:162 or .C:186 or .C:188 or .C:192 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:218 or .C:223 or .C:227 or .C:230; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR69
3.382
ILE73
3.899
SER153
4.753
TYR155
3.627
THR159
3.690
PHE162
4.222
ARG186
4.845
TRP188
4.836
LEU192
3.773
LEU199
4.318
GLY202
3.220
|
|||||
| PDB ID: 7C9I Human gamma-secretase in complex with small molecule L-685,458 | ||||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [2] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:66 or .C:69 or .C:73 or .C:155 or .C:159 or .C:162 or .C:188 or .C:192 or .C:198 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:223 or .C:224 or .C:226 or .C:227 or .C:230; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
ARG66
4.728
TYR69
3.701
ILE73
3.713
TYR155
3.849
THR159
3.868
PHE162
3.809
TRP188
4.422
LEU192
3.739
LEU198
4.969
LEU199
3.606
GLY202
3.264
LEU203
4.269
|
|||||
| PDB ID: 7Y5Z CryoEM structure of human PS2-containing gamma-secretase | ||||||
| Method | Electron microscopy | Resolution | 3.40 Å | Mutation | No | [4] |
| PDB Sequence |
GAAVFFGCTF
11 VAFGPAFALF21 LITVAGDPLR31 VIILVAGAFF41 WLVSLLLASV51 VWFILVHVTD 61 RSDARLQYGL71 LIFGAAVSVL81 LQEVFRFAYY91 KLLKKADEGL101 ASLSEDGRSP 111 ISIRQMAYVS121 GLSFGIISGV131 FSVINILADA141 LGPGVVGIHG151 DSPYYFLTSA 161 FLTAAIILLH171 TFWGVVFFDA181 CERRRYWALG191 LVVGSHLLTS201 GLTFLNPWYE 211 ASLLPIYAVT221 VSMGLWAFIT231 AGGSLRSIQR241 SLL
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .CLR or .CLR2 or .CLR3 or :3CLR;style chemicals stick;color identity;select .C:69 or .C:73 or .C:153 or .C:155 or .C:159 or .C:162 or .C:186 or .C:188 or .C:192 or .C:196 or .C:198 or .C:199 or .C:202 or .C:203 or .C:205 or .C:206 or .C:210 or .C:211 or .C:214 or .C:215 or .C:220 or .C:223 or .C:224 or .C:227 or .C:230; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR69
3.712
ILE73
3.733
SER153
4.604
TYR155
3.962
THR159
4.509
PHE162
4.364
ARG186
4.431
TRP188
3.683
LEU192
4.211
SER196
3.757
LEU198
4.897
LEU199
4.522
GLY202
3.322
|
|||||
| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Recognition of the amyloid precursor protein by human Gamma-secretase. Science. 2019 Feb 15;363(6428):eaaw0930. | ||||
| REF 2 | Structural basis of Gamma-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14. | ||||
| REF 3 | Structural basis of Notch recognition by human Gamma-secretase. Nature. 2019 Jan;565(7738):192-197. | ||||
| REF 4 | Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. | ||||
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