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- PDB-8vhd: Crystal Structure of Human IDH1 R132Q in complex with NADPH and I... -

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Basic information

Entry
Database: PDB / ID: 8vhd
TitleCrystal Structure of Human IDH1 R132Q in complex with NADPH and Isocitrate
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE
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 ...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 / glyoxylate cycle / response to steroid hormone / female gonad development / peroxisomal matrix / tricarboxylic acid cycle / glutathione metabolic process / Peroxisomal protein import / peroxisome / NAD binding / tertiary granule lumen / NADP binding / secretory granule lumen / ficolin-1-rich granule lumen / response to oxidative stress / cadherin binding / Neutrophil degranulation / magnesium ion binding / protein homodimerization activity / mitochondrion / extracellular exosome / extracellular region / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Isocitrate dehydrogenase NADP-dependent / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase
Similarity search - Domain/homology
ISOCITRIC ACID / IODIDE ION / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsMealka, M. / Sohl, C.D. / Huxford, T.
Funding support United States, 2items
OrganizationGrant numberCountry
American Cancer SocietyRSG-19-075-01-TBE United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 GM137773 United States
CitationJournal: Nat Commun / Year: 2024
Title: Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, ...Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, S. / Schiffer, J.M. / Huxford, T. / Sohl, C.D.
History
DepositionDec 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,20321
Polymers194,0004
Non-polymers4,20217
Water14,430801
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,9139
Polymers97,0002
Non-polymers1,9137
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9030 Å2
ΔGint-78 kcal/mol
Surface area33430 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,28912
Polymers97,0002
Non-polymers2,28910
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10780 Å2
ΔGint-73 kcal/mol
Surface area32020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.408, 103.894, 108.272
Angle α, β, γ (deg.)90.00, 98.54, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / ...IDH / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 48500.117 Da / Num. of mol.: 4 / Mutation: R132Q
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 , 6 types, 818 molecules

#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ICT / ISOCITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C6H8O7 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 801 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 50.76 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100mM Bis-tris propane, 200mM Sodium Iodide, 24%(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.38→39.18 Å / Num. obs: 72042 / % possible obs: 96.88 % / Redundancy: 2 % / CC1/2: 0.996 / Net I/σ(I): 5.28
Reflection shellResolution: 2.38→2.46 Å / Num. unique obs: 6981 / CC1/2: 0.496

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.38→39.18 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2199 3456 4.8 %
Rwork0.1687 --
obs0.1711 72042 96.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.38→39.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13057 0 237 801 14095
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00213628
X-RAY DIFFRACTIONf_angle_d0.45418422
X-RAY DIFFRACTIONf_dihedral_angle_d6.3771816
X-RAY DIFFRACTIONf_chiral_restr0.041981
X-RAY DIFFRACTIONf_plane_restr0.0032342
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.38-2.410.27311040.2212248X-RAY DIFFRACTION78
2.41-2.440.31071170.21372487X-RAY DIFFRACTION89
2.44-2.480.2751270.20822511X-RAY DIFFRACTION87
2.48-2.520.26181400.20682504X-RAY DIFFRACTION90
2.52-2.560.2311440.2042750X-RAY DIFFRACTION98
2.56-2.60.27931270.20912824X-RAY DIFFRACTION99
2.6-2.650.27241680.20612794X-RAY DIFFRACTION99
2.65-2.70.28041400.19632786X-RAY DIFFRACTION99
2.7-2.760.26341540.19722775X-RAY DIFFRACTION99
2.76-2.820.27681420.19242829X-RAY DIFFRACTION99
2.82-2.880.24561520.19182801X-RAY DIFFRACTION99
2.88-2.950.27851370.19322798X-RAY DIFFRACTION99
2.95-3.030.2841330.19662816X-RAY DIFFRACTION99
3.03-3.120.24731250.19312819X-RAY DIFFRACTION98
3.12-3.220.23181420.18762665X-RAY DIFFRACTION96
3.22-3.340.24051570.17052795X-RAY DIFFRACTION98
3.34-3.470.20431370.16052773X-RAY DIFFRACTION99
3.47-3.630.21351510.15042822X-RAY DIFFRACTION99
3.63-3.820.19781430.14672842X-RAY DIFFRACTION99
3.82-4.060.18281370.1422818X-RAY DIFFRACTION99
4.06-4.370.171390.12842826X-RAY DIFFRACTION99
4.37-4.810.15491320.12882729X-RAY DIFFRACTION95
4.81-5.510.19571260.14312873X-RAY DIFFRACTION99
5.51-6.930.18081500.17162830X-RAY DIFFRACTION99
6.93-39.180.161320.14812871X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: -25.1006 Å / Origin y: -1.9002 Å / Origin z: -15.4535 Å
111213212223313233
T0.1431 Å2-0.0019 Å2-0.0171 Å2-0.122 Å2-0.0005 Å2--0.1895 Å2
L0.056 °20.02 °2-0.0623 °2-0.094 °20.0827 °2--0.374 °2
S0.0164 Å °-0.0297 Å °0.0076 Å °-0.0138 Å °0.0201 Å °-0.0206 Å °-0.0098 Å °0.059 Å °-0.0368 Å °
Refinement TLS groupSelection details: all

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