PDB-8hb9: Crystal Structure of Human IDH1 R132H Mutant in Complex with NADP...

ID or keywords:

Entry

Database: PDB / ID: 8hb9

Title

Crystal Structure of Human IDH1 R132H Mutant in Complex with NADPH and Compound IHMT-IDH1-053

Components

Isocitrate dehydrogenase [NADP] cytoplasmic

Keywords

OXIDOREDUCTASE

Function / homology

Function and homology information

Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate / regulation of phospholipid catabolic process / NADPH regeneration / 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 /

MOLECULAR REPLACEMENT / Resolution: 2.8 Å

Authors

Guo, G. / Wang, B. / Liu, J. / Liu, Q.

Funding support

China, 6items

Organization	Grant number	Country
National Natural Science Foundation of China (NSFC)	81703007	China
National Natural Science Foundation of China (NSFC)	81603123	China
National Natural Science Foundation of China (NSFC)	81673469	China
National Natural Science Foundation of China (NSFC)	81773777	China
National Natural Science Foundation of China (NSFC)	81872748	China
National Natural Science Foundation of China (NSFC)	81803366	China

Citation

Journal: Eur.J.Med.Chem. / Year: 2023
Title: Structure-based discovery of IHMT-IDH1-053 as a potent irreversible IDH1 mutant selective inhibitor.
Authors: Liang, Q. / Wang, B. / Zou, F. / Guo, G. / Wang, W. / Wang, W. / Liu, Q. / Shen, L. / Hu, C. / Wang, W. / Wang, A. / Huang, T. / He, Y. / Xia, R. / Ge, J. / Liu, J. / Liu, Q.

History

Deposition	Oct 27, 2022	Deposition site: PDBJ / Processing site: PDBE
Revision 1.0	May 24, 2023	Provider: repository / Type: Initial release
Revision 1.1	May 31, 2023	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2	Feb 7, 2024	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	8hb9.cif.gz	345.4 KB	Display	PDBx/mmCIF format
PDB format	pdb8hb9.ent.gz		Display	PDB format
PDBx/mmJSON format	8hb9.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/hb/8hb9 ftp://data.pdbj.org/pub/pdb/validation_reports/hb/8hb9	HTTPS FTP

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Related structure data

Related structure data	6b0zS S: Starting model for refinement
Similar structure data	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) #34 - Oct 2002 Dihydrofolate Reductase similarity (1) #57 - Sep 2004 Catalase similarity (1)

Deposited unit

AAA: Isocitrate dehydrogenase [NADP] cytoplasmic

BBB: Isocitrate dehydrogenase [NADP] cytoplasmic

CCC: Isocitrate dehydrogenase [NADP] cytoplasmic

DDD: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

194 kDa, 4 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

DDD: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

AAA: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

defined by author
Evidence: gel filtration
97.3 kDa, 2 polymers

2

AAA: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

DDD: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

defined by author
97.3 kDa, 2 polymers

3

BBB: Isocitrate dehydrogenase [NADP] cytoplasmic

CCC: Isocitrate dehydrogenase [NADP] cytoplasmic

hetero molecules

defined by author
96.5 kDa, 2 polymers

Unit cell

Length a, b, c (Å)	84.759, 76.426, 171.971
Angle α, β, γ (deg.)	90.000, 98.270, 90.000
Int Tables number	4
Space group name H-M	P12₁1

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	AAA
2	1	BBB
3	2	AAA
4	2	CCC
5	3	AAA
6	3	DDD
7	4	BBB
8	4	CCC
9	5	BBB
10	5	DDD
11	6	CCC
12	6	DDD

NCS domain segments:

Beg auth comp-ID: LYS / Beg label comp-ID: LYS / Refine code: 1

Dom-ID	Component-ID	Ens-ID	End auth comp-ID	End label comp-ID	Auth asym-ID	Label asym-ID	Auth seq-ID	Label seq-ID
1	1	1	ALA	ALA	AAA	A	3 - 412	3 - 412
2	1	1	ALA	ALA	BBB	B	3 - 412	3 - 412
3	2	2	ALA	ALA	AAA	A	3 - 412	3 - 412
4	2	2	ALA	ALA	CCC	C	3 - 412	3 - 412
5	3	3	ALA	ALA	AAA	A	3 - 410	3 - 410
6	3	3	ALA	ALA	DDD	D	3 - 410	3 - 410
7	4	4	ALA	ALA	BBB	B	3 - 412	3 - 412
8	4	4	ALA	ALA	CCC	C	3 - 412	3 - 412
9	5	5	GLN	GLN	BBB	B	3 - 411	3 - 411
10	5	5	GLN	GLN	DDD	D	3 - 411	3 - 411
11	6	6	ALA	ALA	CCC	C	3 - 410	3 - 410
12	6	6	ALA	ALA	DDD	D	3 - 410	3 - 410

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6
4	Local NCS retraints between domains: 7 8
5	Local NCS retraints between domains: 9 10
6	Local NCS retraints between domains: 11 12

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Protein , 1 types, 4 molecules AAABBBCCCDDD

#1: Protein	Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / Cytosolic NADP-isocitrate dehydrogenase / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase Mass: 46701.176 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IDH1, PICD / Production host: Escherichia coli (E. coli) References: UniProt: O75874, isocitrate dehydrogenase (NADP+)

#1: Protein

Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / Cytosolic NADP-isocitrate dehydrogenase / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase

Mass: 46701.176 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: IDH1, PICD / Production host:

Escherichia coli (E. coli)
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)

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Non-polymers , 5 types, 272 molecules

#2: Chemical	ChemComp-R1R / [2-[2-[[1-[4-[(1S)-1-[[5-fluoranyl-4-[(4S)-2-oxidanylidene-4-propan-2-yl-1,3-oxazolidin-3-yl]pyrimidin-2-yl]amino]ethyl]phenyl]piperidin-4-yl]sulfamoyl]ethylsulfanylmethyl]-3-oxidanylidene-propyl]-trimethyl-azanium Mass: 694.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₃₂H₄₉FN₇O₅S₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₂₁H₃₀N₇O₁₇P₃ / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C₃H₈O₃
#5: Chemical	ChemComp-PEG / DI(HYDROXYETHYL)ETHER Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C₄H₁₀O₃
#6: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 252 / Source method: isolated from a natural source / Formula: H₂O

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Details

Has ligand of interest	Y

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 3.05 Å³/Da / Density % sol: 59.67 %
Crystal grow	Temperature: 315 K / Method: vapor diffusion, sitting drop / Details: 24% PEG 3350, 8% Tacsimate pH 6.0

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5406 Å
Detector	Type: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Apr 15, 2022
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.5406 Å / Relative weight: 1
Reflection	Resolution: 2.8→13.078 Å / Num. obs: 53443 / % possible obs: 99 % / Redundancy: 4.1 % / R_merge(I) obs: 0.11 / Net I/σ(I): 8.8
Reflection shell	Resolution: 2.8→2.89 Å / R_merge(I) obs: 0.606 / Num. unique obs: 4636

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
CrysalisPro		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 6b0z

6b0z

Resolution: 2.8→13.078 Å / Cor.coef. F_o:F_c: 0.916 / Cor.coef. F_o:F_c free: 0.895 / SU B: 16.165 / SU ML: 0.292 / Cross valid method: FREE R-VALUE / ESU R Free: 0.357
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2433	2624	4.912 %
R_work	0.2165	50799	-
all	0.218	-	-
obs	-	53423	98.855 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 41.89 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-2.025 Å²	0 Å²	0.332 Å²
2-	-	3.625 Å²	0 Å²
3-	-	-	-1.628 Å²

Refinement step

Cycle: LAST / Resolution: 2.8→13.078 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	12782	0	269	252	13303

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.004	0.013	13438
X-RAY DIFFRACTION	r_bond_other_d	0.003	0.016	12717
X-RAY DIFFRACTION	r_angle_refined_deg	1.227	1.663	18167
X-RAY DIFFRACTION	r_angle_other_deg	1.171	1.608	29386
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.679	5	1624
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	32.821	23.731	646
X-RAY DIFFRACTION	r_dihedral_angle_other_2_deg	2.94	10	4
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.624	15	2373
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	17.367	15	53
X-RAY DIFFRACTION	r_chiral_restr	0.037	0.2	1770
X-RAY DIFFRACTION	r_chiral_restr_other	1.778	0.2	48
X-RAY DIFFRACTION	r_gen_planes_refined	0.003	0.02	14974
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	2984
X-RAY DIFFRACTION	r_nbd_refined	0.167	0.2	2172
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.15	0.2	10879
X-RAY DIFFRACTION	r_nbtor_refined	0.15	0.2	6287
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.08	0.2	6161
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.128	0.2	296
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.051	0.2	2
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.126	0.2	42
X-RAY DIFFRACTION	r_nbd_other	0.198	0.2	150
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.104	0.2	10
X-RAY DIFFRACTION	r_mcbond_it	1.168	4.439	6430
X-RAY DIFFRACTION	r_mcbond_other	1.166	4.438	6429
X-RAY DIFFRACTION	r_mcangle_it	2.088	6.65	8025
X-RAY DIFFRACTION	r_mcangle_other	2.088	6.651	8026
X-RAY DIFFRACTION	r_scbond_it	0.913	4.542	7008
X-RAY DIFFRACTION	r_scbond_other	0.913	4.542	7009
X-RAY DIFFRACTION	r_scangle_it	1.685	6.747	10125
X-RAY DIFFRACTION	r_scangle_other	1.685	6.747	10126
X-RAY DIFFRACTION	r_lrange_it	3.928	49.72	14159
X-RAY DIFFRACTION	r_lrange_other	3.909	49.757	14131
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.075	0.05	12856
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.071	0.05	12830
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.082	0.05	12695
X-RAY DIFFRACTION	r_ncsr_local_group_4	0.07	0.05	12830
X-RAY DIFFRACTION	r_ncsr_local_group_5	0.079	0.05	12755
X-RAY DIFFRACTION	r_ncsr_local_group_6	0.075	0.05	12678

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	AAA	X-RAY DIFFRACTION	Local ncs	0.07457	0.05009
1	2	BBB	X-RAY DIFFRACTION	Local ncs	0.07457	0.05009
2	3	AAA	X-RAY DIFFRACTION	Local ncs	0.07128	0.05009
2	4	CCC	X-RAY DIFFRACTION	Local ncs	0.07128	0.05009
3	5	AAA	X-RAY DIFFRACTION	Local ncs	0.08226	0.05009
3	6	DDD	X-RAY DIFFRACTION	Local ncs	0.08226	0.05009
4	7	BBB	X-RAY DIFFRACTION	Local ncs	0.06959	0.05009
4	8	CCC	X-RAY DIFFRACTION	Local ncs	0.06959	0.05009
5	9	BBB	X-RAY DIFFRACTION	Local ncs	0.07887	0.05009
5	10	DDD	X-RAY DIFFRACTION	Local ncs	0.07887	0.05009
6	11	CCC	X-RAY DIFFRACTION	Local ncs	0.07544	0.05009
6	12	DDD	X-RAY DIFFRACTION	Local ncs	0.07544	0.05009

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
2.8-2.873	0.367	194	0.348	3741	X-RAY DIFFRACTION	99.595
2.873-2.951	0.363	189	0.328	3707	X-RAY DIFFRACTION	99.9743
2.951-3.037	0.35	169	0.307	3586	X-RAY DIFFRACTION	100
3.037-3.13	0.299	136	0.284	3511	X-RAY DIFFRACTION	100
3.13-3.233	0.314	175	0.264	3366	X-RAY DIFFRACTION	100
3.233-3.346	0.292	187	0.245	3247	X-RAY DIFFRACTION	99.9418
3.346-3.473	0.258	172	0.242	3150	X-RAY DIFFRACTION	99.9398
3.473-3.614	0.247	152	0.223	3013	X-RAY DIFFRACTION	100
3.614-3.775	0.274	137	0.224	2919	X-RAY DIFFRACTION	99.9673
3.775-3.959	0.235	148	0.207	2776	X-RAY DIFFRACTION	99.9316
3.959-4.173	0.224	122	0.193	2678	X-RAY DIFFRACTION	100
4.173-4.426	0.195	130	0.171	2514	X-RAY DIFFRACTION	100
4.426-4.732	0.179	152	0.155	2351	X-RAY DIFFRACTION	100
4.732-5.11	0.187	125	0.161	2186	X-RAY DIFFRACTION	100
5.11-5.598	0.232	98	0.191	2046	X-RAY DIFFRACTION	100
5.598-6.258	0.252	102	0.195	1835	X-RAY DIFFRACTION	100
6.258-7.224	0.192	95	0.179	1637	X-RAY DIFFRACTION	100
7.224-8.844	0.174	75	0.149	1383	X-RAY DIFFRACTION	100
8.844-12.49	0.156	64	0.144	1092	X-RAY DIFFRACTION	100

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