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- PDB-5l58: Crystal structure of Iso-citrate Dehydrogenase 1 [IDH1 (R132H)] i... -

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Basic information

Entry
Database: PDB / ID: 5l58
TitleCrystal structure of Iso-citrate Dehydrogenase 1 [IDH1 (R132H)] in complex with a novel inhibitor (Compound 2)
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE / 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 / tricarboxylic acid cycle / glutathione metabolic process / Peroxisomal protein import / NAD binding / peroxisome / 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 / 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-6MX / Chem-NDP / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.04 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)47,6713
Polymers46,4121
Non-polymers1,2592
Water00
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,3426
Polymers92,8242
Non-polymers2,5184
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_557y,x,-z+21
Buried area5830 Å2
ΔGint-34 kcal/mol
Surface area33400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.166, 72.166, 179.829
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


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


Mass: 513.692 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H39N3O4S

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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: 2.52 Å3/Da / Density % sol: 51.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 200nl of protein with 200nl of a reservoir solution of 0.06M Divalents, 0.1M Tris / Bicine pH 8.5, 50% (40% v/v PEG 500 MME, 20% w/v PEG 20K) [Morpheus E9]
Temp details: Cold room

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9795 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: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3.04→66.97 Å / Num. obs: 9699 / % possible obs: 99 % / Redundancy: 5.9 % / CC1/2: 0.835 / Rmerge(I) obs: 0.1997 / Net I/σ(I): 7.3
Reflection shellResolution: 3.04→3.149 Å / Redundancy: 2.01 % / Rmerge(I) obs: 0.9098 / Mean I/σ(I) obs: 2.01 / % possible all: 100

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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: 3.04→66.97 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 30.32
RfactorNum. reflection% reflection
Rfree0.2636 497 5.13 %
Rwork0.2303 --
obs0.232 9680 99.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.04→66.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2918 0 84 0 3002
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023066
X-RAY DIFFRACTIONf_angle_d0.4184145
X-RAY DIFFRACTIONf_dihedral_angle_d11.4111815
X-RAY DIFFRACTIONf_chiral_restr0.04459
X-RAY DIFFRACTIONf_plane_restr0.003518
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.0401-3.34610.30931330.29312200X-RAY DIFFRACTION99
3.3461-3.83020.27941130.22732260X-RAY DIFFRACTION99
3.8302-4.82550.21361130.2052295X-RAY DIFFRACTION99
4.8255-66.99080.2721380.22732428X-RAY DIFFRACTION99
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)
10.7076-0.0970.41390.9104-0.41312.4987-0.03950.13730.11530.05530.1592-0.0687-0.49120.068-0.12870.3625-0.08340.02510.28880.0070.33992.666645.4232187.2527
20.8923-0.608-0.84750.48630.38661.1127-0.0234-0.1360.2384-0.20770.0250.05140.20310.39730.01880.3450.0839-0.02810.44220.01150.339221.991530.4451186.9571
31.77070.05290.02961.95370.07341.1163-0.17720.1226-0.1805-0.0070.0778-0.34960.31180.61670.14060.40920.12630.00870.58830.00820.434921.255822.402194.6531
41.4550.581-0.39121.0716-0.5271.1124-0.120.23360.0232-0.26370.13290.06750.3019-0.0576-0.05010.3220.05140.03930.26770.00880.272-5.585130.2741187.8445
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 111 )
2X-RAY DIFFRACTION2chain 'A' and (resid 112 through 203 )
3X-RAY DIFFRACTION3chain 'A' and (resid 204 through 287 )
4X-RAY DIFFRACTION4chain 'A' and (resid 288 through 414 )

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