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- PDB-6bkz: Novel Modes of Inhibition of Wild-Type IDH1: Non-equivalent Allos... -

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Basic information

Entry
Database: PDB / ID: 6bkz
TitleNovel Modes of Inhibition of Wild-Type IDH1: Non-equivalent Allosteric Inhibition with Cmpd3
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
Keywordsoxidoreductase/oxidoreductase inhibitor / dehydrogenase / inhibitor / OXIDOREDUCTASE / oxidoreductase-oxidoreductase inhibitor complex
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 / NADPH regeneration / 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 / NADPH regeneration / NADP+ metabolic process / 2-oxoglutarate metabolic process / glyoxylate cycle / response to steroid hormone / female gonad development / peroxisomal matrix / tricarboxylic acid cycle / glutathione metabolic process / Peroxisomal protein import / NAD binding / tertiary granule lumen / peroxisome / NADP binding / response to oxidative stress / secretory granule lumen / 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-DWM / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsJakob, C.G. / Qiu, W.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.
Authors: Jakob, C.G. / Upadhyay, A.K. / Donner, P.L. / Nicholl, E. / Addo, S.N. / Qiu, W. / Ling, C. / Gopalakrishnan, S.M. / Torrent, M. / Cepa, S.P. / Shanley, J. / Shoemaker, A.R. / Sun, C.C. / ...Authors: Jakob, C.G. / Upadhyay, A.K. / Donner, P.L. / Nicholl, E. / Addo, S.N. / Qiu, W. / Ling, C. / Gopalakrishnan, S.M. / Torrent, M. / Cepa, S.P. / Shanley, J. / Shoemaker, A.R. / Sun, C.C. / Vasudevan, A. / Woller, K.R. / Shotwell, J.B. / Shaw, B. / Bian, Z. / Hutti, J.E.
History
DepositionNov 9, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 25, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 22, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 2023Group: 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)98,7996
Polymers96,3092
Non-polymers2,4904
Water13,277737
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8240 Å2
ΔGint-46 kcal/mol
Surface area34810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)83.463, 83.463, 299.255
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-727-

HOH

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Components

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


Mass: 48154.730 Da / Num. of mol.: 2
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+)
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-DWM / (7R)-1-[(4-fluorophenyl)methyl]-N-{3-[(1R)-1-hydroxyethyl]phenyl}-7-methyl-5-(1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide


Mass: 501.552 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H28FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 737 / 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: 2.71 Å3/Da / Density % sol: 54.54 %
Crystal growTemperature: 290 K / Method: vapor diffusion
Details: 18% PEG8K, 0.2M Calcium Acetate, 0.1M Na Cacodylate pH6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 13, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.01→299.25 Å / Num. obs: 71566 / % possible obs: 100 % / Redundancy: 12.5 % / Biso Wilson estimate: 36.33 Å2 / Rmerge(I) obs: 0.114 / Net I/σ(I): 16.9
Reflection shellResolution: 2.012→2.019 Å / Redundancy: 12.3 % / Rmerge(I) obs: 1.222 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 706 / % possible all: 97

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UMX

4umx


Resolution: 2.01→80.39 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.146 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.16 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflectionSelection details
Rfree0.204 3555 4.98 %RANDOM
Rwork0.173 ---
obs0.175 71431 100 %-
Displacement parametersBiso mean: 38.56 Å2
Baniso -1Baniso -2Baniso -3
1-0.2006 Å20 Å20 Å2
2--0.2006 Å20 Å2
3----0.4012 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: 1 / Resolution: 2.01→80.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6532 0 170 737 7439
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016854HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.069268HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2448SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1250HARMONIC5
X-RAY DIFFRACTIONt_it6854HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion17.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion886SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8305SEMIHARMONIC4
LS refinement shellResolution: 2.01→2.06 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2579 229 4.42 %
Rwork0.2048 4957 -
all0.2072 5186 -
obs--99.98 %

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