PDB-5i96: Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase...

ID or keywords:

Entry

Database: PDB / ID: 5i96

Title

Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase (IDH2) R140Q Mutant Homodimer in Complex with AG-221 (Enasidenib) Inhibitor.

Components

Isocitrate dehydrogenase [NADP], mitochondrial

Keywords

OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / IDH / IDH2 / enasidenib / AG-221 / IDH2 AG-221 / ICD-M / IDP NADP(+)-specific ICDH Oxalosuccinate decarboxylase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex

Function / homology

Function and homology information

negative regulation of glial cell migration / negative regulation of matrix metallopeptidase secretion / Citric acid cycle (TCA cycle) / Maturation of TCA enzymes and regulation of TCA cycle / NADP+ biosynthetic process / isocitrate metabolic process / isocitrate dehydrogenase (NADP+) / isocitrate dehydrogenase (NADP+) activity / NADP+ metabolic process / 2-oxoglutarate metabolic process ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.55 Å

Authors

Wei, W. / Zhang, B. / Jin, L. / Jiang, F. / DeLaBarre, B. / Travins, J.A. / Padyana, A.K.

Citation

Journal: Cancer Discov / Year: 2017
Title: AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.
Authors: Yen, K. / Travins, J. / Wang, F. / David, M.D. / Artin, E. / Straley, K. / Padyana, A. / Gross, S. / DeLaBarre, B. / Tobin, E. / Chen, Y. / Nagaraja, R. / Choe, S. / Jin, L. / Konteatis, Z. ...

History

Deposition	Feb 19, 2016	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Mar 8, 2017	Provider: repository / Type: Initial release
Revision 1.1	May 10, 2017	Group: Database references
Revision 1.2	Jul 5, 2017	Group: Database references / Structure summary / Category: entity / struct_ref_seq_dif / Item: _entity.pdbx_mutation / _struct_ref_seq_dif.details
Revision 1.3	Sep 20, 2017	Group: Structure summary / Item: _chem_comp.pdbx_synonyms
Revision 1.4	Sep 27, 2023	Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	5i96.cif.gz	387.5 KB	Display	PDBx/mmCIF format
PDB format	pdb5i96.ent.gz	314.3 KB	Display	PDB format
PDBx/mmJSON format	5i96.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	5i96_validation.pdf.gz	1.7 MB	Display	wwPDB validaton report
Full document	5i96_full_validation.pdf.gz	1.8 MB	Display
Data in XML	5i96_validation.xml.gz	43.9 KB	Display
Data in CIF	5i96_validation.cif.gz	66.9 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/i9/5i96 ftp://data.pdbj.org/pub/pdb/validation_reports/i9/5i96	HTTPS FTP

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Related structure data

Related structure data	5i95C 4ja8S C: citing same article (ref.) S: Starting model for refinement
Similar structure data	4ja8-d 6aja-1 1diq-d 2qfv-2 6vg0-1 5svo-d 3zx2-1 6vfz-d 6aj8-d 6adg-1 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) #34 - Oct 2002 Dihydrofolate Reductase similarity (1) #57 - Sep 2004 Catalase similarity (1)

Deposited unit

A: Isocitrate dehydrogenase [NADP], mitochondrial

B: Isocitrate dehydrogenase [NADP], mitochondrial

hetero molecules

106 kDa, 2 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	58.368, 120.348, 124.734
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

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Protein , 1 types, 2 molecules AB

#1: Protein	Isocitrate dehydrogenase [NADP], mitochondrial / IDH / ICD-M / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase Mass: 51783.008 Da / Num. of mol.: 2 / Mutation: R140Q Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IDH2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P48735, isocitrate dehydrogenase (NADP+)

#1: Protein

Isocitrate dehydrogenase [NADP], mitochondrial / IDH / ICD-M / IDP / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase

Mass: 51783.008 Da / Num. of mol.: 2 / Mutation: R140Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.)

Homo sapiens (human) / Gene: IDH2 / Cell line (production host): SF9 / Production host:

Spodoptera frugiperda (fall armyworm)
References: UniProt: P48735, isocitrate dehydrogenase (NADP+)

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Non-polymers , 7 types, 993 molecules

#2: Chemical	ChemComp-CA / CALCIUM ION Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#3: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C₃H₈O₃
#4: Chemical	ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₁H₃₀N₇O₁₇P₃
#5: Chemical	ChemComp-NA / SODIUM ION Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical	ChemComp-ACT / ACETATE ION Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₃O₂
#7: Chemical	ChemComp-69Q / 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol / Enasidenib / AG-221 Mass: 473.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₉H₁₇F₆N₇O
#8: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 979 / 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: 2.12 Å³/Da / Density % sol: 41.85 %
Crystal grow	Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M Tris-HCl, pH 8.5, 0.25 M CaCl2, 25% PEG4000

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Data collection

Diffraction

Mean temperature: 100 K

Diffraction source

Source:

SYNCHROTRON / Site:

SSRF

/ Beamline: BL17U / Wavelength: 0.9793 Å

Detector

Type: ADSC QUANTUM 315r / Detector: CCD

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.9793 Å / Relative weight: 1

Reflection

Resolution: 1.55→48.4 Å / Num. obs: 121589 / % possible obs: 95 % / Redundancy: 4.5 % / R_merge(I) obs: 0.052 / R_pim(I) all: 0.028 / R_rim(I) all: 0.059 / Χ²: 1.078 / Net I/av σ(I): 24.353 / Net I/σ(I): 12.5 / Num. measured all: 543881

Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique all	CC_1/2	R_pim(I) all	R_rim(I) all	Χ²	% possible all
1.55-1.61	4.3	0.504	11883	0.789	0.274	0.576	1.076	94.1
1.61-1.67	4.4	0.383	11795	0.868	0.206	0.437	1.108	93.1
1.67-1.75	4.4	0.292	11742	0.922	0.156	0.333	1.115	92.9
1.75-1.84	4.5	0.208	11621	0.962	0.11	0.236	1.127	91.6
1.84-1.95	4.5	0.143	11598	0.981	0.076	0.163	1.198	91.1
1.95-2.1	4.4	0.091	11938	0.992	0.048	0.103	1.087	94
2.1-2.32	4.5	0.064	12402	0.996	0.034	0.073	1.087	97
2.32-2.65	4.6	0.051	12633	0.997	0.027	0.058	1.06	98.3
2.65-3.34	4.6	0.038	12759	0.998	0.02	0.043	1.041	98.9
3.34-50	4.4	0.024	13218	0.999	0.013	0.027	0.911	98.9

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Processing

Software

Name	Version	Classification
PHENIX	1.11.1_2575	refinement
HKL-2000	1.98.7	data scaling
PDB_EXTRACT	3.2	data extraction
HKL-2000	1.98.7	data reduction

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 4JA8

4ja8

Resolution: 1.55→41.896 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.76 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.1988	6152	5.06 %	RANDOM
R_work	0.1632	-	-	-
obs	0.165	121515	94.99 %	-

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL

Refinement step

Cycle: LAST / Resolution: 1.55→41.896 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	6555	0	171	979	7705

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	7400
X-RAY DIFFRACTION	f_angle_d	0.944	10083
X-RAY DIFFRACTION	f_dihedral_angle_d	15.355	4403
X-RAY DIFFRACTION	f_chiral_restr	0.054	1075
X-RAY DIFFRACTION	f_plane_restr	0.006	1294

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 (%)
1.55-1.5676	0.2745	207	0.2311	3662	X-RAY DIFFRACTION	92
1.5676-1.5861	0.2347	165	0.2171	3789	X-RAY DIFFRACTION	94
1.5861-1.6054	0.2441	193	0.2052	3809	X-RAY DIFFRACTION	95
1.6054-1.6257	0.2408	181	0.1914	3723	X-RAY DIFFRACTION	93
1.6257-1.6471	0.2178	190	0.191	3797	X-RAY DIFFRACTION	94
1.6471-1.6697	0.2118	170	0.1855	3741	X-RAY DIFFRACTION	93
1.6697-1.6935	0.2074	221	0.183	3695	X-RAY DIFFRACTION	93
1.6935-1.7188	0.2093	217	0.179	3705	X-RAY DIFFRACTION	93
1.7188-1.7457	0.2051	201	0.1756	3702	X-RAY DIFFRACTION	93
1.7457-1.7743	0.2309	199	0.1751	3719	X-RAY DIFFRACTION	92
1.7743-1.8049	0.2234	199	0.1769	3645	X-RAY DIFFRACTION	91
1.8049-1.8377	0.2043	198	0.165	3683	X-RAY DIFFRACTION	92
1.8377-1.8731	0.2109	186	0.17	3609	X-RAY DIFFRACTION	90
1.8731-1.9113	0.2014	196	0.1673	3702	X-RAY DIFFRACTION	91
1.9113-1.9528	0.2031	228	0.1692	3660	X-RAY DIFFRACTION	92
1.9528-1.9983	0.2037	220	0.1691	3686	X-RAY DIFFRACTION	93
1.9983-2.0482	0.1998	183	0.1618	3839	X-RAY DIFFRACTION	94
2.0482-2.1036	0.2213	194	0.1633	3822	X-RAY DIFFRACTION	95
2.1036-2.1655	0.1882	212	0.1594	3861	X-RAY DIFFRACTION	95
2.1655-2.2354	0.1924	229	0.1597	3917	X-RAY DIFFRACTION	97
2.2354-2.3153	0.2071	202	0.1571	3989	X-RAY DIFFRACTION	98
2.3153-2.408	0.2087	196	0.1644	4006	X-RAY DIFFRACTION	98
2.408-2.5176	0.2007	207	0.1696	3994	X-RAY DIFFRACTION	98
2.5176-2.6503	0.2116	227	0.1758	3991	X-RAY DIFFRACTION	98
2.6503-2.8163	0.2177	234	0.1667	3981	X-RAY DIFFRACTION	99
2.8163-3.0337	0.2005	209	0.1721	4073	X-RAY DIFFRACTION	99
3.0337-3.3389	0.1965	202	0.1609	4054	X-RAY DIFFRACTION	98
3.3389-3.8217	0.1938	194	0.1418	4113	X-RAY DIFFRACTION	99
3.8217-4.8139	0.1508	224	0.1294	4144	X-RAY DIFFRACTION	99
4.8139-41.9116	0.1874	268	0.1641	4252	X-RAY DIFFRACTION	99

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	1.1086	0.202	-0.101	1.1282	-0.1805	0.74	-0.0336	-0.193	-0.0765	0.1322	0.0398	-0.0767	0.0316	0.0218	0.0105	0.0918	0.0129	-0.0188	0.1173	0.0119	0.0842	13.62	5.9419	1.9122
2	0.9658	0.1815	0.1636	0.506	0.0538	0.44	-0.0284	0.0286	-0.0505	-0.2043	0.0317	-0.0359	0.0194	0.0022	0.0094	0.116	-0.0214	0.02	0.1058	-0.0163	0.0935	7.4204	9.154	-13.1455
3	0.5775	-0.127	-0.1898	0.6439	0.4243	0.9693	-0.0151	-0.013	-0.0363	-0.0633	-0.0145	0.0229	-0.0093	-0.0326	0.0035	0.0725	-0.0032	-0.0003	0.0841	-0.0119	0.0818	-10.7566	4.6873	-19.921
4	0.6476	-0.1466	0.0744	0.8625	0.0904	0.2027	0.0074	-0.0009	0.1709	-0.0037	0.0146	0.0102	-0.0248	-0.0036	-0.0252	0.0735	-0.0069	-0.0041	0.0937	-0.0102	0.1027	12.0765	20.971	-4.2424
5	1.6406	-0.2254	0.3226	0.8959	0.1482	0.9664	-0.0281	0.2607	-0.0361	-0.7097	-0.2928	0.4182	-0.2837	-0.2809	0.1633	0.3642	0.1013	-0.2506	0.318	-0.1779	0.3083	-16.7004	18.153	-50.0053
6	0.6537	0.0637	-0.326	0.6347	-0.011	1.001	0.013	0.077	-0.0477	-0.0604	-0.0279	-0.0022	0.0419	0.0786	-0.0008	0.1279	0.0085	0.006	0.1228	-0.0388	0.0978	-0.3602	2.1178	-37.0674
7	1.4159	0.112	0.4191	1.5384	0.2664	0.9574	-0.2721	0.6248	0.6352	-0.5411	-0.4087	0.4738	-0.6139	0.0749	0.1893	0.5666	0.0959	-0.2916	0.1315	0.0139	0.3935	-10.1988	29.9994	-47.9142

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	chain 'A' and (resid 41 through 119 )
2	X-RAY DIFFRACTION	2	chain 'A' and (resid 120 through 172 )
3	X-RAY DIFFRACTION	3	chain 'A' and (resid 173 through 323 )
4	X-RAY DIFFRACTION	4	chain 'A' and (resid 324 through 457 )
5	X-RAY DIFFRACTION	5	chain 'B' and (resid 43 through 172 )
6	X-RAY DIFFRACTION	6	chain 'B' and (resid 173 through 323 )
7	X-RAY DIFFRACTION	7	chain 'B' and (resid 324 through 449 )

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