Target Binding Site Detail
Target General Information | Top | ||||
---|---|---|---|---|---|
Target ID | T88569 | Target Info | |||
Target Name | Mutated oxalosuccinate decarboxylase (mIDH1) | ||||
Synonyms | PICD (mutated); Oxalosuccinate decarboxylase (mutated); NADP(+)-specific ICDH (mutated); Isocitrate dehydrogenase [NADP] cytoplasmic (mutated); IDP (mutated); IDH (mutated); Cytosolic NADP-isocitrate dehydrogenase (mutated) | ||||
Target Type | Clinical trial Target | ||||
Gene Name | IDH1 | ||||
Biochemical Class | Short-chain dehydrogenases reductase | ||||
UniProt ID |
Ligand General Information | Top | ||||
---|---|---|---|---|---|
Ligand Name | NADPH | Ligand Info | |||
Canonical SMILES | C1C=CN(C=C1C(=O)N)C2C(C(C(O2)COP(=O)(O)OP(=O)(O)OCC3C(C(C(O3)N4C=NC5=C(N=CN=C54)N)OP(=O)(O)O)O)O)O | ||||
InChI | 1S/C21H30N7O17P3/c22-17-12-19(25-7-24-17)28(8-26-12)21-16(44-46(33,34)35)14(30)11(43-21)6-41-48(38,39)45-47(36,37)40-5-10-13(29)15(31)20(42-10)27-3-1-2-9(4-27)18(23)32/h1,3-4,7-8,10-11,13-16,20-21,29-31H,2,5-6H2,(H2,23,32)(H,36,37)(H,38,39)(H2,22,24,25)(H2,33,34,35)/t10-,11-,13-,14-,15-,16-,20-,21-/m1/s1 | ||||
InChIKey | ACFIXJIJDZMPPO-NNYOXOHSSA-N | ||||
PubChem Compound ID | 5884 |
Drug Binding Sites of Target | Top | |||||
---|---|---|---|---|---|---|
PDB ID: 6IO0 Human IDH1 R132C mutant complexed with compound A. | ||||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [1] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGC132 HRATDFVVPG148 PGKVEITYTP158 SDGTQKVTYL 168 VHNFEEGGGV178 AMGMYNQDKS188 IEDFAHSSFQ198 MALSKGWPLY208 LSTKNTILKK 218 YDGRFKDIFQ228 EIYDKQYKSQ238 FEAQKIWYEH248 RLIDDMVAQA258 MKSEGGFIWA 268 CKVQSDSVAQ283 GYGSLGMMTS293 VLVCPDGKTV303 EAEAAHGTVT313 RHYRMYQKGQ 323 ETSTNPIASI333 FAWTRGLAHR343 AKLDNNKELA353 FFANALEEVS363 IETIEAGFMT 373 KDLAACIKGL383 PNVQRSDYLN393 TFEFMDKLGE403 NLKIKLAQAK413 |
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|
GLU17
4.704
LYS72
3.352
CYS73
4.607
ALA74
3.502
THR75
2.920
ILE76
3.796
THR77
2.985
ARG82
3.216
ASN96
3.363
GLN283
4.094
LEU288
3.761
GLY289
4.002
GLU306
3.088
ALA307
3.876
|
|||||
PDB ID: 5L57 Crystal structure of Iso-citrate Dehydrogenase R132H in complex with a novel inhibitor (compound 13a) | ||||||
Method | X-ray diffraction | Resolution | 2.69 Å | Mutation | Yes | [2] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDAAR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 TYLVHNFEEG175 GGVAMGMYNQ185 DKSIEDFAHS195 SFQMALSKGW205 PLYLSTKNTI 215 LKKYDGRFKD225 IFQEIYDKQY235 KSQFAAAAIW245 YEHRLIDDMV255 AQAMKSEGGF 265 IWACKNYDGD275 VQSDSVAQGY285 GSLGMMTSVL295 VCPDGKTVEA305 EAAHGTVTRH 315 YRMYQKGQET325 STNPIASIFA335 WTRGLAHRAK345 LDNNKELAFF355 ANALEEVSIE 365 TIEAGFMTKD375 LAACIKGLPN385 VQRSDYLNTF395 EFMDKLGENL405 KIKLAQAKL |
|||||
|
LYS72
4.348
ALA74
4.042
THR75
2.883
ILE76
3.427
THR77
2.897
ARG82
3.052
ASN96
3.156
ASP279
3.630
SER280
3.431
GLN283
4.601
LEU288
3.409
GLY289
3.879
GLU306
2.928
|
|||||
PDB ID: 5L58 Crystal structure of Iso-citrate Dehydrogenase 1 [IDH1 (R132H)] in complex with a novel inhibitor (Compound 2) | ||||||
Method | X-ray diffraction | Resolution | 3.04 Å | Mutation | Yes | [2] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDAAR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGATDFVV146 PGPEITTYLV169 GGVAMGMYNQ 185 DKSIEDFAHS195 SFQMALSKGW205 PLYLSTKKYD220 GRFKDIFQEI230 YDKQYKSQFA 240 AAAIWYEHRL250 IDDMVAQAMK260 SEGGFIWACK270 NYVAQGYGSL288 GMMTSVLVCP 298 DGKTVEAEAA308 HGTVTRHYRM318 YQKGQETSTN328 PIASIFAWTR338 GLAHRAKLDN 348 NKELAFFANA358 LEEVSIETIE368 AGFMTKDLAA378 CIKGLPNVQR388 SDYLNTFEFM 398 DKLGENLKIK408 LAQAKL
|
|||||
|
LYS72
3.341
CYS73
4.754
ALA74
3.962
THR75
3.050
ILE76
3.904
THR77
2.951
ARG82
3.595
ASN96
3.057
VAL281
4.453
LEU288
3.517
GLY289
3.513
GLU306
3.325
ALA307
3.923
|
|||||
PDB ID: 4XRX Crystal structure of a metabolic reductase with (E)-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one | ||||||
Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | Yes | [3] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HYRATDFVVP147 GPGKVEITYT157 PSDGTQKVTY 167 LVHNFEEGGG177 VAMGMYNQDK187 SIEDFAHSSF197 QMALSKGWPL207 YLSTKNTILK 217 KYDGRFKDIF227 QEIYDKQYKS237 QFEAQKIWYE247 HRLIDDMVAQ257 AMKSEGGFIW 267 ACKSLGMMTS293 VLVCPDGKTV303 EAEAAHGTVT313 RHYRMYQKGQ323 ETSTNPIASI 333 FAWTRGLAHR343 AKLDNNKELA353 FFANALEEVS363 IETIEAGFMT373 KDLAACIKGL 383 PNVQRSDYLN393 TFEFMDKLGE403 NLKIKLAQAK413
|
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.765
LYS72
3.094
ALA74
3.934
THR75
2.925
ILE76
3.925
THR77
3.040
ARG82
3.425
ASN96
3.669
LEU288
3.395
GLY289
3.842
GLU306
3.974
ALA307
4.442
|
|||||
PDB ID: 4I3L Crystal structure of a metabolic reductase with 6-benzyl-1-hydroxy-4-methylpyridin-2(1H)-one | ||||||
Method | X-ray diffraction | Resolution | 3.29 Å | Mutation | Yes | [4] |
PDB Sequence |
KISGGSVVEM
13 QGDEMTRIIW23 ELIKEKLIFP33 YVELDLHSYD43 LGIENRDATN53 DQVTKDAAEA 63 IKKHNVGVKC73 ATITPDEKRV83 EEFKLKQMWK93 SPNGTIRNIL103 GGTVFREAII 113 CKNPIIIGHH133 ATDFVVPGPG150 KVEITYTPSD160 GTQKVTYLVH170 NFEEGGGVAM 180 GMYNQDKSIE190 DFAHSSFQMA200 LSKGWPLYLS210 TKNTILKKYD220 GRFKDIFQEI 230 YDKQYKSQFE240 AQKIWYEHRL250 IDDMVGFIWA268 CKNLGMMTSV294 LVCPDGKTVE 304 AEAAHGTVTR314 HYRMYQKGQE324 TSTNPIASIF334 AWTRGLAHRA344 KLDNNKELAF 354 FANALEEVSI364 ETIEAGFMTK374 DLAACIKGLP384 NVQRSDYLNT394 FEFMDKLGEN 404 LKIKLAQ
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.700
LYS72
2.951
CYS73
4.745
ALA74
3.381
THR75
2.580
ILE76
3.762
THR77
2.679
ARG82
3.369
ASN96
3.753
LEU288
3.558
GLY289
3.718
GLU306
3.384
ALA307
4.334
|
|||||
PDB ID: 4I3K Crystal structure of a metabolic reductase with 1-hydroxy-6-(4-hydroxybenzyl)-4-methylpyridin-2(1H)-one | ||||||
Method | X-ray diffraction | Resolution | 3.31 Å | Mutation | Yes | [4] |
PDB Sequence |
KISGGSVVEM
13 QGDEMTRIIW23 ELIKEKLIFP33 YVELDLHSYD43 LGIENRDATN53 DQVTKDAAEA 63 IKKHNVGVKC73 ATITPDEKRV83 EEFKLKQMWK93 SPNGTIRNIL103 GGTVFREAII 113 CKNPIIIGHH133 ATDFVVPGPG150 KVEITYTPSD160 GTQKVTYLVH170 NFEEGGGVAM 180 GMYNQDKSIE190 DFAHSSFQMA200 LSKGWPLYLS210 TKNTILKKYD220 GRFKDIFQEI 230 YDKQYKSQFE240 AQKIWYEHRL250 IDDMVGFIWA268 CKNLGMMTSV294 LVCPDGKTVE 304 AEAAHGTVTR314 HYRMYQKGQE324 TSTNPIASIF334 AWTRGLAHRA344 KLDNNKELAF 354 FANALEEVSI364 ETIEAGFMTK374 DLAACIKGLP384 NVQRSDYLNT394 FEFMDKLGEN 404 LKIKLAQ
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:79 or .A:82 or .A:94 or .A:95 or .A:96 or .A:288 or .A:289 or .A:306 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.858
LYS72
2.964
CYS73
4.464
ALA74
3.332
THR75
2.406
ILE76
4.020
THR77
2.970
ASP79
4.999
ARG82
3.171
SER94
4.961
PRO95
4.043
ASN96
2.933
LEU288
4.165
GLY289
3.823
|
|||||
PDB ID: 5TQH IDH1 R132H mutant in complex with IDH889 | ||||||
Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [5] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAQYRATDFV145 VPGPGKVEIT155 YTPSDGTQKV 165 TYLVHNFEEG175 GGVAMGMYNQ185 DKSIEDFAHS195 SFQMALSKGW205 PLYLSTKNTI 215 LKKYDGRFKD225 IFQEIYDKQY235 KSQFEAQKIW245 YEHRLIDDMV255 AQAMKSEGGF 265 IWACKNSDSV281 AQGYGSLGMM291 TSVLVCPDGK301 TVEAEAAHGT311 VTRHYRMYQK 321 GQETSTNPIA331 SIFAWTRGLA341 HRAKLDNNKE351 LAFFANALEE361 VSIETIEAGF 371 MTKDLAACIK381 GLPNVQRSDY391 LNTFEFMDKL401 GENLKIKLAQ411 A |
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:283 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.691
LYS72
3.433
CYS73
4.718
ALA74
3.469
THR75
3.039
ILE76
3.711
THR77
3.027
ARG82
3.104
ASN96
3.472
GLN283
3.662
LEU288
3.398
GLY289
3.770
GLU306
3.573
|
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PDB ID: 6B0Z IDH1 R132H mutant in complex with IDH305 | ||||||
Method | X-ray diffraction | Resolution | 2.33 Å | Mutation | Yes | [6] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAATDFVVPG148 PGKVEITYTP158 SDGTQKVTYL 168 VHNFEEGGGV178 AMGMYNQDKS188 IEDFAHSSFQ198 MALSKGWPLY208 LSTKNTILKK 218 YDGRFKDIFQ228 EIYDKQYKSQ238 FEAQKIWYEH248 RLIDDMVAQA258 MKSEGGFIWA 268 CKNQSDSVAQ283 GYGSLGMMTS293 VLVCPDGKTV303 EAEAAHGTVT313 RHYRMYQKGQ 323 ETSTNPIASI333 FAWTRGLAHR343 AKLDNNKELA353 FFANALEEVS363 IETIEAGFMT 373 KDLAACIKGL383 PNVQRSDYLN393 TFEFMDKLGE403 NLKIKLAQA
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:283 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.661
LYS72
3.602
CYS73
4.866
ALA74
3.607
THR75
3.043
ILE76
3.860
THR77
2.953
ARG82
3.239
ASN96
3.271
GLN283
3.967
LEU288
3.654
GLY289
3.821
GLU306
3.923
|
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PDB ID: 5SVF IDH1 R132H in complex with IDH125 | ||||||
Method | X-ray diffraction | Resolution | 2.34 Å | Mutation | Yes | [7] |
PDB Sequence |
KISGGSVVEM
13 QGDEMTRIIW23 ELIKEKLIFP33 YVELDLHSYD43 LGIENRDATN53 DQVTKDAAEA 63 IKKHNVGVKC73 ATITPDEKRV83 EEFKLKQMWK93 SPNGTIRNIL103 GGTVFREAII 113 CKNIPRLVSG123 WVKPIIIGHH133 AATDFVVPGP149 GKVEITYTPS159 DGTQKVTYLV 169 HNFEEGGGVA179 MGMYNQDKSI189 EDFAHSSFQM199 ALSKGWPLYL209 STKNTILKKY 219 DGRFKDIFQE229 IYDKQYKSQF239 EAQKIWYEHR249 LIDDMVAQAM259 KSEGGFIWAC 269 KNQSDSVAQG284 YGSLGMMTSV294 LVCPDGKTVE304 AEAAHGTVTR314 HYRMYQKGQE 324 TSTNPIASIF334 AWTRGLAHRA344 KLDNNKELAF354 FANALEEVSI364 ETIEAGFMTK 374 DLAACIKGLP384 NVQRSDYLNT394 FEFMDKLGEN404 LKIKLAQA
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:283 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.720
LYS72
3.634
CYS73
4.863
ALA74
3.593
THR75
3.001
ILE76
3.810
THR77
3.029
ARG82
3.043
ASN96
3.228
GLN283
3.796
LEU288
3.634
GLY289
3.809
GLU306
3.382
|
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PDB ID: 5SUN IDH1 R132H in complex with IDH146 | ||||||
Method | X-ray diffraction | Resolution | 2.48 Å | Mutation | Yes | [7] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 ATDFVVPGPG150 KVEITYTPSD160 GTQKVTYLVH 170 NFEEGGGVAM180 GMYNQDKSIE190 DFAHSSFQMA200 LSKGWPLYLS210 TKNTILKKYD 220 GRFKDIFQEI230 YDKQYKSQFE240 AQKIWYEHRL250 IDDMVAQAMK260 SEGGFIWACK 270 NSLGMMTSVL295 VCPDGKTVEA305 EAAHGTVTRH315 YRMYQKGQET325 STNPIASIFA 335 WTRGLAHRAK345 LDNNKELAFF355 ANALEEVSIE365 TIEAGFMTKD375 LAACIKGLPN 385 VQRSDYLNTF395 EFMDKLGENL405 KIKLAQAK
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.553
LYS72
3.475
CYS73
4.949
ALA74
3.739
THR75
2.981
ILE76
3.589
THR77
2.891
ARG82
3.067
ASN96
3.394
LEU288
3.796
GLY289
3.882
GLU306
3.578
ALA307
4.369
|
|||||
PDB ID: 7PJM Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and Ca2+/2-Oxoglutarate | ||||||
Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [8] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGC132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDFVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLLEH
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:19 or .A:22 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:95 or .A:96 or .A:100 or .A:283 or .A:287 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:329 or .A:330 or .A:331 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
3.551
THR19
4.871
ILE22
4.610
LYS72
2.257
CYS73
4.101
ALA74
2.545
THR75
1.804
ILE76
2.050
THR77
2.371
ARG82
2.337
PRO95
4.978
ASN96
2.029
ARG100
4.354
GLN283
4.862
SER287
4.625
LEU288
2.520
GLY289
3.164
|
|||||
PDB ID: 8BAY Crystal Structure of IDH1 variant R132C S280F in complex with NADPH, Ca2+ and 3-butyl-2-oxoglutarate | ||||||
Method | X-ray diffraction | Resolution | 2.35 Å | Mutation | Yes | [9] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGC132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDFVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLLE
|
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.819
LYS72
4.465
ALA74
4.210
THR75
3.192
ILE76
3.278
THR77
3.074
ARG82
3.126
ASN96
3.554
ALA307
4.251
ALA308
2.997
HIS309
3.278
|
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PDB ID: 7PJN Crystal Structure of Ivosidenib-resistant IDH1 variant R132C S280F in complex with NADPH and inhibitor DS-1001B | ||||||
Method | X-ray diffraction | Resolution | 2.45 Å | Mutation | Yes | [8] |
PDB Sequence |
> Chain A
KKISGGSVVE 12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGC132 HAYRATDFVV146 PGPGKVEITY156 TPSDGTQKVT 166 YLVHNFEEGG176 GVAMGMYNQD186 KSIEDFAHSS196 FQMALSKGWP206 LYLSTKNTIL 216 KKYDGRFKDI226 FQEIYDKQYK236 SQFEAQKIWY246 EHRLIDDMVA256 QAMKSEGGFI 266 WACKNYDGDV276 QSDFVAQGYG286 SLGMMTSVLV296 CPDGKTVEAE306 AAHGTVTRHY 316 RMYQKGQETS326 TNPIASIFAW336 TRGLAHRAKL346 DNNKELAFFA356 NALEEVSIET 366 IEAGFMTKDL376 AACIKGLPNV386 QRSDYLNTFE396 FMDKLGENLK406 IKLAQA > Chain B SKKISGGSVV 11 EMQGDEMTRI21 IWELIKEKLI31 FPYVELDLHS41 YDLGIENRDA51 TNDQVTKDAA 61 EAIKKHNVGV71 KCATITPDEK81 RVEEFKLKQM91 WKSPNGTIRN101 ILGGTVFREA 111 IICKNIPRLV121 SGWVKPIIIG131 CHARATDFVV146 PGPGKVEITY156 TPSDGTQKVT 166 YLVHNFEEGG176 GVAMGMYNQD186 KSIEDFAHSS196 FQMALSKGWP206 LYLSTKNTIL 216 KKYDGRFKDI226 FQEIYDKQYK236 SQFEAQKIWY246 EHRLIDDMVA256 QAMKSEGGFI 266 WACKNYDGDV276 QSDFVAQGYG286 SLGMMTSVLV296 CPDGKTVEAE306 AAHGTVTRHY 316 RMYQKGQETS326 TNPIASIFAW336 TRGLAHRAKL346 DNNKELAFFA356 NALEEVSIET 366 IEAGFMTKDL376 AAIKGLPNVQ387 RSDYLNTFEF397 MDKLGENLKI407 KLAQ |
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:19 or .A:22 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:100 or .A:109 or .A:283 or .A:286 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:329 or .A:330 or .A:331 or .A:375 or .B:17 or .B:19 or .B:22 or .B:72 or .B:73 or .B:74 or .B:75 or .B:76 or .B:77 or .B:82 or .B:96 or .B:100 or .B:283 or .B:286 or .B:288 or .B:289 or .B:306 or .B:307 or .B:308 or .B:309 or .B:310 or .B:311 or .B:312 or .B:313 or .B:314 or .B:315 or .B:326 or .B:327 or .B:328 or .B:329 or .B:331 or .B:373 or .B:375 or .B:383; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17[A]
3.712
THR19[A]
4.987
ILE22[A]
4.343
LYS72[A]
2.827
CYS73[A]
4.525
ALA74[A]
2.559
THR75[A]
2.090
ILE76[A]
2.837
THR77[A]
2.424
ARG82[A]
2.124
ASN96[A]
2.456
ARG100[A]
4.652
ARG109[A]
4.946
GLN283[A]
3.009
GLY286[A]
4.837
LEU288[A]
2.374
GLY289[A]
3.048
GLU306[A]
3.095
ALA307[A]
4.143
ALA308[A]
3.335
HIS309[A]
2.419
GLY310[A]
2.008
THR311[A]
2.159
VAL312[A]
1.616
THR313[A]
2.387
ARG314[A]
1.819
HIS315[A]
1.995
SER326[A]
3.757
THR327[A]
2.623
ASN328[A]
1.889
PRO329[A]
4.019
ILE330[A]
4.995
ALA331[A]
4.533
ASP375[A]
2.802
GLU17[B]
3.406
THR19[B]
4.665
ILE22[B]
4.606
LYS72[B]
2.845
CYS73[B]
4.700
ALA74[B]
2.703
THR75[B]
2.034
ILE76[B]
2.688
THR77[B]
2.362
ARG82[B]
2.112
ASN96[B]
2.208
ARG100[B]
4.058
GLN283[B]
2.877
GLY286[B]
4.591
LEU288[B]
2.854
GLY289[B]
3.085
GLU306[B]
3.016
ALA307[B]
4.117
ALA308[B]
3.354
HIS309[B]
2.505
GLY310[B]
2.066
THR311[B]
2.160
VAL312[B]
1.868
THR313[B]
2.448
ARG314[B]
2.249
HIS315[B]
1.873
SER326[B]
3.838
THR327[B]
2.626
ASN328[B]
1.876
PRO329[B]
4.022
ALA331[B]
4.597
THR373[B]
4.909
ASP375[B]
2.827
LEU383[B]
4.482
|
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PDB ID: 3INM Crystal structure of human cytosolic NADP(+)-dependent isocitrate dehydrogenase R132H mutant in complex with NADPH, ALPHA-KETOGLUTARATE and CALCIUM(2+) | ||||||
Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [10] |
PDB Sequence |
KISGGSVVEM
13 QGDEMTRIIW23 ELIKEKLIFP33 YVELDLHSYD43 LGIENRDATN53 DQVTKDAAEA 63 IKKHNVGVKC73 ATITPDEKRV83 EEFKLKQMWK93 SPNGTIRNIL103 GGTVFREAII 113 CKNIPRLVSG123 WVKPIIIGHH133 AYGDQYRATD143 FVVPGPGKVE153 ITYTPSDGTQ 163 KVTYLVHNFE173 EGGGVAMGMY183 NQDKSIEDFA193 HSSFQMALSK203 GWPLYLSTKN 213 TILKKYDGRF223 KDIFQEIYDK233 QYKSQFEAQK243 IWYEHRLIDD253 MVAQAMKSEG 263 GFIWACKNYD273 GDVQSDSVAQ283 GYGSLGMMTS293 VLVCPDGKTV303 EAEAAHGTVT 313 RHYRMYQKGQ323 ETSTNPIASI333 FAWTRGLAHR343 AKLDNNKELA353 FFANALEEVS 363 IETIEAGFMT373 KDLAACIKGL383 PNVQRSDYLN393 TFEFMDKLGE403 NLKIKLA |
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:287 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.670
LYS72
3.699
CYS73
4.792
ALA74
3.546
THR75
2.840
ILE76
3.744
THR77
3.371
ARG82
3.026
ASN96
2.870
SER287
4.751
LEU288
3.515
GLY289
4.211
GLU306
4.684
|
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PDB ID: 6VEI Crystal Structure of Human Cytosolic Isocitrate Dehydrogenase (IDH1) R132H Mutant in Complex with NADPH and AG-881 (Vorasidenib) Inhibitor | ||||||
Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [11] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KLS
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:287 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.632
LYS72
3.555
CYS73
4.922
ALA74
3.682
THR75
2.998
ILE76
3.773
THR77
3.125
ARG82
3.138
ASN96
2.922
SER287
4.608
LEU288
3.642
GLY289
3.631
GLU306
3.240
|
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PDB ID: 6VG0 CRYSTAL STRUCTURE OF HUMAN CYTOSOLIC ISOCITRATE DEHYDROGENASE (IDH1) R132H MUTANT IN COMPLEX WITH NADPH and AGI-15056 | ||||||
Method | X-ray diffraction | Resolution | 2.66 Å | Mutation | Yes | [11] |
PDB Sequence |
SKKISGGSVV
11 EMQGDEMTRI21 IWELIKEKLI31 FPYVELDLHS41 YDLGIENRDA51 TNDQVTKDAA 61 EAIKKHNVGV71 KCATITPDEK81 RVEEFKLKQM91 WKSPNGTIRN101 ILGGTVFREA 111 IICKNIPRLV121 SGWVKPIIIG131 HHAYGDQYRA141 TDFVVPGPGK151 VEITYTPSDG 161 TQKVTYLVHN171 FEEGGGVAMG181 MYNQDKSIED191 FAHSSFQMAL201 SKGWPLYLST 211 KNTILKKYDG221 RFKDIFQEIY231 DKQYKSQFEA241 QKIWYEHRLI251 DDMVAQAMKS 261 EGGFIWACKN271 YDGDVQSDSV281 AQGYGSLGMM291 TSVLVCPDGK301 TVEAEAAHGT 311 VTRHYRMYQK321 GQETSTNPIA331 SIFAWTRGLA341 HRAKLDNNKE351 LAFFANALEE 361 VSIETIEAGF371 MTKDLAACIK381 GLPNVQRSDY391 LNTFEFMDKL401 GENLKIKLAQ 411 AKL
|
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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 .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:73 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:287 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:375; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.925
LYS72
3.607
CYS73
4.729
ALA74
3.680
THR75
3.062
ILE76
3.905
THR77
3.323
ARG82
3.279
ASN96
3.229
SER287
4.858
LEU288
3.819
GLY289
3.755
GLU306
3.204
|
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PDB ID: 6ADG Crystal Structures of IDH1 R132H in complex with AG-881 | ||||||
Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | Yes | [12] |
PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGH132 HAYGDQYRAT142 DFVVPGPGKV152 EITYTPSDGT 162 QKVTYLVHNF172 EEGGGVAMGM182 YNQDKSIEDF192 AHSSFQMALS202 KGWPLYLSTK 212 NTILKKYDGR222 FKDIFQEIYD232 KQYKSQFEAQ242 KIWYEHRLID252 DMVAQAMKSE 262 GGFIWACKNY272 DGDVQSDSVA282 QGYGSLGMMT292 SVLVCPDGKT302 VEAEAAHGTV 312 TRHYRMYQKG322 QETSTNPIAS332 IFAWTRGLAH342 RAKLDNNKEL352 AFFANALEEV 362 SIETIEAGFM372 TKDLAACIKG382 LPNVQRSDYL392 NTFEFMDKLG402 ENLKIKLAQA 412 KL
|
|||||
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .NDP or .NDP2 or .NDP3 or :3NDP;style chemicals stick;color identity;select .A:17 or .A:72 or .A:74 or .A:75 or .A:76 or .A:77 or .A:82 or .A:96 or .A:287 or .A:288 or .A:289 or .A:306 or .A:307 or .A:308 or .A:309 or .A:310 or .A:311 or .A:312 or .A:313 or .A:314 or .A:315 or .A:326 or .A:327 or .A:328 or .A:329 or .A:375; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
GLU17
4.690
LYS72
3.929
ALA74
3.827
THR75
3.329
ILE76
3.727
THR77
3.178
ARG82
3.161
ASN96
2.900
SER287
4.747
LEU288
3.863
GLY289
3.769
GLU306
3.691
ALA307
3.367
|
References | Top | ||||
---|---|---|---|---|---|
REF 1 | A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model. Mol Cancer Ther. 2020 Feb;19(2):375-383. | ||||
REF 2 | Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells. J Med Chem. 2016 Dec 22;59(24):11120-11137. | ||||
REF 3 | Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds. J Med Chem. 2015 Sep 10;58(17):6899-6908. | ||||
REF 4 | Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase. ACS Med Chem Lett. 2013 Jun 13;4(6):542-546. | ||||
REF 5 | Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1. ACS Med Chem Lett. 2016 Dec 16;8(2):151-156. | ||||
REF 6 | Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor. ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121. | ||||
REF 7 | Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity. Structure. 2017 Mar 7;25(3):506-513. | ||||
REF 8 | Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors. Nat Commun. 2022 Aug 15;13(1):4785. | ||||
REF 9 | Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2. J Biol Chem. 2023 Feb;299(2):102873. | ||||
REF 10 | Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10;462(7274):739-44. | ||||
REF 11 | Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma. ACS Med Chem Lett. 2020 Jan 22;11(2):101-107. | ||||
REF 12 | Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2912-2917. |
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