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- PDB-5l57: Crystal structure of Iso-citrate Dehydrogenase R132H in complex w... -

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Basic information

Entry
Database: PDB / ID: 5l57
TitleCrystal structure of Iso-citrate Dehydrogenase R132H in complex with a novel inhibitor (compound 13a)
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE / R132H / Iso-citrate Dehydrogenase / Allosteric
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 / glutathione metabolic process / tricarboxylic acid cycle / Peroxisomal protein import / peroxisome / NAD binding / tertiary granule lumen / NADP binding / secretory granule lumen / response to oxidative stress / ficolin-1-rich granule lumen / cadherin binding / Neutrophil degranulation / magnesium ion binding / protein homodimerization activity / mitochondrion / extracellular exosome / extracellular region / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Isocitrate dehydrogenase NADP-dependent / Isopropylmalate Dehydrogenase / Isopropylmalate Dehydrogenase / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-6N3 / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.695 Å
AuthorsLevy, C.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
Authors: Jones, S. / Ahmet, J. / Ayton, K. / Ball, M. / Cockerill, M. / Fairweather, E. / Hamilton, N. / Harper, P. / Hitchin, J. / Jordan, A. / Levy, C. / Lopez, R. / McKenzie, E. / Packer, M. / ...Authors: Jones, S. / Ahmet, J. / Ayton, K. / Ball, M. / Cockerill, M. / Fairweather, E. / Hamilton, N. / Harper, P. / Hitchin, J. / Jordan, A. / Levy, C. / Lopez, R. / McKenzie, E. / Packer, M. / Plant, D. / Simpson, I. / Simpson, P. / Sinclair, I. / Somervaille, T.C. / Small, H. / Spencer, G.J. / Thomson, G. / Tonge, M. / Waddell, I. / Walsh, J. / Waszkowycz, B. / Wigglesworth, M. / Wiseman, D.H. / Ogilvie, D.
History
DepositionMay 28, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 14, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2017Group: Database references
Revision 1.2Oct 9, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)47,6413
Polymers46,4121
Non-polymers1,2292
Water34219
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,2826
Polymers92,8242
Non-polymers2,4584
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_557y,x,-z+21
Buried area8080 Å2
ΔGint-44 kcal/mol
Surface area33730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.866, 72.866, 182.642
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 46411.852 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDH1, PICD / Plasmid: pET22b / Production host: Escherichia coli (E. coli) / Strain (production host): JM109 (DE3)
References: UniProt: O75874, isocitrate dehydrogenase (NADP+)
#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-6N3 / (1~{R},5~{S})-3-[6-(3-methylbutoxy)-5-[[(1~{R},3~{S})-5-oxidanyl-2-adamantyl]carbamoyl]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid


Mass: 483.600 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H37N3O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O

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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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.12M Ethylene Glycols, 0.1M Bicine pH 8.5, 50% (40% v/v PEG 500 MME, 20% w/v PEG 20K) [Morpheus A9] 200 plus 200nl drops (Mosquito)
Temp details: Cold Room

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 2.695→46.72 Å / Num. obs: 14266 / % possible obs: 100 % / Redundancy: 12.7 % / CC1/2: 1 / Rmerge(I) obs: 0.07166 / Net I/σ(I): 27.39
Reflection shellResolution: 2.695→2.791 Å / Redundancy: 12.8 % / Rmerge(I) obs: 0.5252 / Mean I/σ(I) obs: 4.65 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Inhouse

Resolution: 2.695→46.72 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.5 / Phase error: 27.82
RfactorNum. reflection% reflection
Rfree0.2557 1415 9.92 %
Rwork0.214 --
obs0.218 14260 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.695→46.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3187 0 83 19 3289
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043361
X-RAY DIFFRACTIONf_angle_d0.6024559
X-RAY DIFFRACTIONf_dihedral_angle_d13.1481988
X-RAY DIFFRACTIONf_chiral_restr0.043498
X-RAY DIFFRACTIONf_plane_restr0.003575
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6951-2.79140.40121360.30181232X-RAY DIFFRACTION99
2.7914-2.90310.36951360.2691240X-RAY DIFFRACTION99
2.9031-3.03520.36051410.26941272X-RAY DIFFRACTION100
3.0352-3.19520.31771380.26151244X-RAY DIFFRACTION100
3.1952-3.39540.30881390.25671271X-RAY DIFFRACTION100
3.3954-3.65740.2941410.23421272X-RAY DIFFRACTION100
3.6574-4.02530.23321390.20151280X-RAY DIFFRACTION100
4.0253-4.60730.20031430.16821293X-RAY DIFFRACTION100
4.6073-5.8030.20521450.17971319X-RAY DIFFRACTION100
5.803-46.72660.2291570.20551422X-RAY DIFFRACTION100
Refinement TLS params.

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

IDL11 (°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)
10.5196-0.28120.5481.66250.01471.9658-0.06790.13860.0685-0.16420.0699-0.0567-0.27050.14350.02640.4394-0.01050.04080.38340.01340.35413.058841.4438189.9679
20.2989-0.1266-0.38320.2413-0.26081.3758-0.057-0.16910.1801-0.09440.0523-0.0428-0.18550.16510.03230.4641-0.0050.07260.5308-0.0840.623532.019734.9304189.4707
34.2131.14361.53592.23561.16123.74-0.3490.0263-0.25840.150.3456-0.39740.06970.87180.06760.47190.1491-0.02060.5838-0.0110.464620.425823.5206196.1774
41.60480.6280.44041.8521-0.19891.8112-0.07680.17930.131-0.21050.11510.11790.25820.0764-0.05550.3440.04830.04770.36160.0090.3284-5.752330.5898190.5805
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 132 )
2X-RAY DIFFRACTION2chain 'A' and (resid 133 through 222 )
3X-RAY DIFFRACTION3chain 'A' and (resid 223 through 287 )
4X-RAY DIFFRACTION4chain 'A' and (resid 288 through 414 )

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