PDB-6o2y: Crystal structure of IDH1 R132H mutant in complex with compound 24

ID or keywords:

Entry

Database: PDB / ID: 6o2y

Title

Crystal structure of IDH1 R132H mutant in complex with compound 24

Components

Isocitrate dehydrogenase [NADP] cytoplasmic

Keywords

Oxidoreductase/Inhibitor / IDH1 / allosteric inhibitor / Oxidoreductase / Inhibitor complex / Oxidoreductase-Inhibitor complex

Function / homology

Function and homology information

Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / NADPH regeneration / regulation of phospholipid catabolic process / regulation of phospholipid biosynthetic process / NFE2L2 regulating TCA cycle genes / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / 2-oxoglutarate metabolic process / NADP metabolic process ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 2.8 Å

Authors

Toms, A.V. / Lin, J.

Citation

Journal: J.Med.Chem. / Year: 2019
Title: Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.
Authors: Lin, J. / Lu, W. / Caravella, J.A. / Campbell, A.M. / Diebold, R.B. / Ericsson, A. / Fritzen, E. / Gustafson, G.R. / Lancia Jr., D.R. / Shelekhin, T. / Wang, Z. / Castro, J. / Clarke, A. / ...

History

Deposition	Feb 25, 2019	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jun 26, 2019	Provider: repository / Type: Initial release
Revision 1.1	Jul 17, 2019	Group: Data collection / Refinement description / Category: pdbx_refine_tls / Item: _pdbx_refine_tls.pdbx_refine_id
Revision 1.2	Aug 7, 2019	Group: Data collection / Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3	Mar 13, 2024	Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	6o2y.cif.gz	502.3 KB	Display	PDBx/mmCIF format
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Validation report

Summary document	6o2y_validation.pdf.gz	2.3 MB	Display	wwPDB validaton report
Full document	6o2y_full_validation.pdf.gz	2.4 MB	Display
Data in XML	6o2y_validation.xml.gz	45.9 KB	Display
Data in CIF	6o2y_validation.cif.gz	61.3 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/o2/6o2y ftp://data.pdbj.org/pub/pdb/validation_reports/o2/6o2y	HTTPS FTP

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Related structure data

Related structure data	6o2zC C: citing same article (ref.)
Similar structure data	1t09-d 2g97-d 4o10-d 5dky-d 3dkl-d 6u4j-d 5wi1-d 2g95-d 6b0z-2 2gvj-d Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Search similar-shape structures by Omokage search (details) Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#129 - Sep 2010 Isocitrate Dehydrogenase similarity (6) #154 - Oct 2012 Citric Acid Cycle similarity (5) #234 - Jun 2019 MDM2 and Cancer similarity (1) #252 - Dec 2020 Hepatitis C Virus Protease/Helicase similarity (1) #9 - Sep 2000 Lysozyme similarity (1)

Deposited unit

A: Isocitrate dehydrogenase [NADP] cytoplasmic

B: Isocitrate dehydrogenase [NADP] cytoplasmic

C: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

148 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Isocitrate dehydrogenase [NADP] cytoplasmic

B: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

defined by author&software
98.6 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

2

C: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

C: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

defined by author&software
98.5 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

Unit cell

Length a, b, c (Å)	165.679, 63.496, 143.598
Angle α, β, γ (deg.)	90.00, 99.52, 90.00
Int Tables number	5
Space group name H-M	C121

#1: Protein	Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / Cytosolic NADP-isocitrate dehydrogenase / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase Mass: 48177.719 Da / Num. of mol.: 3 / Mutation: R132H Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IDH1, PICD / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2(DE3) References: UniProt: O75874, isocitrate dehydrogenase (NADP+)
#2: Chemical	ChemComp-LJY / 4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile Mass: 339.776 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₁₈H₁₄ClN₃O₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE Mass: 743.405 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₂₁H₂₈N₇O₁₇P₃
#4: Chemical	ChemComp-BME / BETA-MERCAPTOETHANOL Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂H₆OS
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 23 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.58 Å³/Da / Density % sol: 52.31 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, sitting drop Details: 20% PEG MME 5000, 0.1 M Bicine pH 8.5, and 0.2 M Sodium formate.

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
Detector	Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 18, 2012
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.075 Å / Relative weight: 1
Reflection	Resolution: 2.8→50 Å / Num. obs: 36650 / % possible obs: 98.6 % / Redundancy: 2.8 % / Net I/σ(I): 15.8
Reflection shell	Resolution: 2.8→2.9 Å

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0158	refinement
DENZO		data reduction
SCALEPACK		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 2.8→50 Å / Cor.coef. F_o:F_c: 0.948 / Cor.coef. F_o:F_c free: 0.914 / Cross valid method: THROUGHOUT / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.2745	1803	5 %	RANDOM
R_work	0.20859	-	-	-
obs	0.21199	34299	98.28 %	-

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å

Displacement parameters

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.23 Å²	0 Å²	0.94 Å²
2-	-	-2.04 Å²	0 Å²
3-	-	-	1.85 Å²

Refinement step

Cycle: 1 / Resolution: 2.8→50 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	9735	0	220	23	9978

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.011	0.019	10177
X-RAY DIFFRACTION	r_bond_other_d	0	0.02	9273
X-RAY DIFFRACTION	r_angle_refined_deg	1.565	1.973	13765
X-RAY DIFFRACTION	r_angle_other_deg	3.79	3	21560
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.015	5	1229
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	38.923	24.858	459
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	21.752	15	1777
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	23.748	15	42
X-RAY DIFFRACTION	r_chiral_restr	0.08	0.2	1477
X-RAY DIFFRACTION	r_gen_planes_refined	0.005	0.02	11211
X-RAY DIFFRACTION	r_gen_planes_other	0.006	0.02	2064
X-RAY DIFFRACTION	r_nbd_refined
X-RAY DIFFRACTION	r_nbd_other
X-RAY DIFFRACTION	r_nbtor_refined
X-RAY DIFFRACTION	r_nbtor_other
X-RAY DIFFRACTION	r_xyhbond_nbd_refined
X-RAY DIFFRACTION	r_xyhbond_nbd_other
X-RAY DIFFRACTION	r_metal_ion_refined
X-RAY DIFFRACTION	r_metal_ion_other
X-RAY DIFFRACTION	r_symmetry_vdw_refined
X-RAY DIFFRACTION	r_symmetry_vdw_other
X-RAY DIFFRACTION	r_symmetry_hbond_refined
X-RAY DIFFRACTION	r_symmetry_hbond_other
X-RAY DIFFRACTION	r_symmetry_metal_ion_refined
X-RAY DIFFRACTION	r_symmetry_metal_ion_other
X-RAY DIFFRACTION	r_mcbond_it	1.045	3.226	4928
X-RAY DIFFRACTION	r_mcbond_other	1.045	3.226	4927
X-RAY DIFFRACTION	r_mcangle_it	1.851	4.835	6153
X-RAY DIFFRACTION	r_mcangle_other	1.851	4.836	6154
X-RAY DIFFRACTION	r_scbond_it	0.954	3.406	5248
X-RAY DIFFRACTION	r_scbond_other	0.954	3.407	5249
X-RAY DIFFRACTION	r_scangle_it
X-RAY DIFFRACTION	r_scangle_other	1.634	5.099	7613
X-RAY DIFFRACTION	r_long_range_B_refined	4.637	37.746	11573
X-RAY DIFFRACTION	r_long_range_B_other	4.637	37.748	11574
X-RAY DIFFRACTION	r_rigid_bond_restr
X-RAY DIFFRACTION	r_sphericity_free
X-RAY DIFFRACTION	r_sphericity_bonded

LS refinement shell

Resolution: 2.8→2.873 Å / Total num. of bins used: 20

	R_factor	Num. reflection	% reflection
R_free	0.337	126	-
R_work	0.333	2525	-
obs	-	-	97.32 %

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°²)	L12 (°²)	L13 (°²)	L22 (°²)	L23 (°²)	L33 (°²)	S11 (Å °)	S12 (Å °)	S13 (Å °)	S21 (Å °)	S22 (Å °)	S23 (Å °)	S31 (Å °)	S32 (Å °)	S33 (Å °)	T11 (Å²)	T12 (Å²)	T13 (Å²)	T22 (Å²)	T23 (Å²)	T33 (Å²)	Origin x (Å)	Origin y (Å)	Origin z (Å)
1	1.1508	-0.2587	-0.3794	3.6653	-1.3954	3.7494	-0.1541	-0.1132	0.2538	0.4916	0.0982	-0.0812	-0.2001	0.537	0.0559	0.4337	-0.0822	-0.1575	0.5603	-0.0081	0.1039	0.08	2.663	54.358
2	1.4253	-1.0167	0.318	3.7449	3.2064	4.7798	0.0349	0.4657	-0.0134	-0.205	-0.0156	0.1655	-0.1055	0.2343	-0.0193	0.5514	-0.0733	-0.1201	0.616	0.0676	0.0693	-15.647	-1.688	37.137
3	0.2189	-0.396	-0.0287	4.2737	0.2839	2.2969	0.2763	-0.2504	0.059	0.516	0.0969	0.2018	0.05	-0.3337	-0.3731	0.8915	-0.1547	0.0878	0.7369	-0.0396	0.1528	-37.407	2.877	65.145
4	3.9006	0.655	0.3471	1.6153	-0.5882	2.6958	0.0884	0.4123	0.3311	0.0074	0.2248	0.1644	-0.264	-0.2329	-0.3132	0.4723	0.0168	-0.0731	0.4689	0.1027	0.1042	-27.267	8.957	40.18
5	1.7809	0.2116	0.1948	1.7398	-0.5092	2.1691	-0.0125	0.536	0.0421	-0.1839	0.0041	-0.0934	0.2213	0.4344	0.0083	0.5598	-0.0159	-0.1529	0.8251	-0.0351	0.0624	-1.313	-4.134	38.396
6	0.8711	-0.0776	-0.8473	3.3336	-0.285	3.3044	0.0798	0.306	0.1849	0.064	-0.1246	0.4921	0.125	-0.7689	0.0448	0.515	-0.2709	-0.1202	1.0149	0.0627	0.208	-54.132	-16.286	37.694
7	2.9392	-0.0213	-2.1997	1.4847	1.5645	6.6023	0.0359	0.0507	-0.4293	0.0754	0.0661	-0.0535	0.2584	-0.0115	-0.102	0.5726	-0.041	-0.2075	0.4719	0.0229	0.1607	-31.006	-21.139	40.326
8	4.046	0.6629	-1.5285	3.2186	-1.7302	2.6465	0.3646	-0.4257	0.4312	0.5007	-0.1283	0.2358	-0.4427	-0.199	-0.2363	0.6624	-0.0399	0.042	0.5289	-0.001	0.0617	-36.519	4.226	64.822
9	2.7507	0.2906	-0.9773	3.1658	0.5585	3.7705	0.0802	-0.1176	-0.1186	0.6065	-0.0219	-0.156	0.6835	0.0429	-0.0583	0.8849	-0.0798	-0.246	0.5155	0.0529	0.0762	-29.176	-20.988	56.041
10	1.9837	0.2519	-0.5318	2.3778	-0.0128	1.5384	-0.0256	0.3164	-0.0049	-0.0581	0.0994	-0.0327	0.6323	-0.4821	-0.0737	0.7751	-0.2721	-0.2168	0.8803	0.0613	0.0728	-40.459	-23.887	29.613
11	0.5672	1.5313	-0.8694	5.4532	-0.1543	6.1622	-0.1238	-0.1401	0.0946	-0.3516	-0.2829	0.2391	-0.0207	-0.6655	0.4067	0.2776	0.224	-0.2855	1.4773	-0.3974	0.3571	-28.557	-31.861	-6.072
12	4.8723	-1.1739	-0.292	2.8366	2.283	3.252	0.0072	-0.7016	-0.0984	0.4085	-0.2093	0.0504	0.506	-0.2801	0.2021	0.4385	-0.0888	-0.1883	1.2191	-0.0467	0.1561	-11.196	-43.115	5.666
13	1.4838	-1.9086	-2.1017	2.7847	3.574	5.5637	0.3518	-0.1973	0.3792	-0.7135	-0.0924	-0.3504	-1.1668	-0.1338	-0.2594	0.6964	-0.0062	-0.2947	0.8679	-0.1158	0.6032	0.705	-9.936	-0.248
14	4.093	-0.9571	1.4424	2.8131	-0.5742	2.8422	-0.171	-0.6644	0.5261	0.4397	-0.37	-0.1192	-0.2994	-0.0176	0.541	0.4514	-0.093	-0.2213	1.3899	-0.187	0.2161	-6.89	-32.237	15.748
15	1.2366	0.4247	0.492	1.9704	0.4393	2.5831	0.3089	-0.7239	0.0576	0.1372	-0.6164	0.1163	0.5185	-0.6274	0.3075	0.5352	-0.0856	-0.1392	1.7369	-0.2293	0.1427	-22.65	-48.256	-1.806

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	A	3 - 102
2	X-RAY DIFFRACTION	2	A	103 - 135
3	X-RAY DIFFRACTION	3	A	136 - 186
4	X-RAY DIFFRACTION	4	A	187 - 275
5	X-RAY DIFFRACTION	5	A	276 - 415
6	X-RAY DIFFRACTION	6	B	4 - 102
7	X-RAY DIFFRACTION	7	B	103 - 135
8	X-RAY DIFFRACTION	8	B	136 - 186
9	X-RAY DIFFRACTION	9	B	187 - 275
10	X-RAY DIFFRACTION	10	B	276 - 414
11	X-RAY DIFFRACTION	11	C	5 - 102
12	X-RAY DIFFRACTION	12	C	103 - 135
13	X-RAY DIFFRACTION	13	C	136 - 186
14	X-RAY DIFFRACTION	14	C	187 - 275
15	X-RAY DIFFRACTION	15	C	276 - 414

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