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 | Alpha-ketoglutaric acid | Ligand Info | |||
| Canonical SMILES | C(CC(=O)O)C(=O)C(=O)O | ||||
| InChI | 1S/C5H6O5/c6-3(5(9)10)1-2-4(7)8/h1-2H2,(H,7,8)(H,9,10) | ||||
| InChIKey | KPGXRSRHYNQIFN-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 51 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| 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 | [1] |
| 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
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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 | [2] |
| 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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| PDB ID: 4KZO Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [3] |
| 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 KLSL
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| PDB ID: 4L06 Crystal Structure Analysis of human IDH1 mutants in complex with NADP+ and Ca2+/alpha-Ketoglutarate | ||||||
| Method | X-ray diffraction | Resolution | 2.28 Å | Mutation | Yes | [3] |
| PDB Sequence |
KKISGGSVVE
12 MQGDEMTRII22 WELIKEKLIF32 PYVELDLHSY42 DLGIENRDAT52 NDQVTKDAAE 62 AIKKHNVGVK72 CATITPDEKR82 VEEFKLKQMW92 KSPNGTIRNI102 LGGTVFREAI 112 ICKNIPRLVS122 GWVKPIIIGR132 HAYGDQDRAT142 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
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | 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 2 | Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10;462(7274):739-44. | ||||
| REF 3 | Mutant IDH1 enhances the production of 2-hydroxyglutarate due to its kinetic mechanism. Biochemistry. 2013 Jul 2;52(26):4563-77. | ||||
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