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- PDB-6bky: Novel Binding Modes of Inhibition of Wild-Type IDH1: Allosteric I... -

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Basic information

Entry
Database: PDB / ID: 6bky
TitleNovel Binding Modes of Inhibition of Wild-Type IDH1: Allosteric Inhibition with Cmpd2
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 / cytoplasm / cytosol
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
4,5,6,7-TETRABROMO-1H,3H-BENZIMIDAZOL-2-ONE / (2S)-2-hydroxybutanedioic acid / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 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 ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / software / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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_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_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 / _software.name / _struct_conn.pdbx_dist_value / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)290,77716
Polymers288,9286
Non-polymers1,84910
Water25,2391401
1
D: Isocitrate dehydrogenase [NADP] cytoplasmic
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,9426
Polymers96,3092
Non-polymers6324
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7450 Å2
ΔGint-69 kcal/mol
Surface area33320 Å2
MethodPISA
2
F: Isocitrate dehydrogenase [NADP] cytoplasmic
E: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,9185
Polymers96,3092
Non-polymers6083
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7350 Å2
ΔGint-60 kcal/mol
Surface area33160 Å2
MethodPISA
3
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,9185
Polymers96,3092
Non-polymers6083
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7320 Å2
ΔGint-61 kcal/mol
Surface area33010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.665, 274.889, 116.798
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number5
Space group name H-MC121

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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.: 6
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-LMR / (2S)-2-hydroxybutanedioic acid / L-Malate


Mass: 134.087 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C4H6O5
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-K32 / 4,5,6,7-TETRABROMO-1H,3H-BENZIMIDAZOL-2-ONE


Mass: 449.720 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C7H2Br4N2O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1401 / 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: 2.82 Å3/Da / Density % sol: 56.39 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7 / Details: 20% PEG3350, 0.15M D,L-Malic acid pH 7.0

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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: Oct 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.17→137.44 Å / Num. obs: 159602 / % possible obs: 97.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 44.17 Å2 / Rmerge(I) obs: 0.084 / Net I/σ(I): 10.1
Reflection shellResolution: 2.171→2.179 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.715 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1667 / % possible all: 96

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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: 2.17→137.44 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.214 / SU Rfree Blow DPI: 0.174 / SU Rfree Cruickshank DPI: 0.175
Details: Note that space group C2 was selected because one ligand was on a 2 fold symmetry axis.
RfactorNum. reflection% reflectionSelection details
Rfree0.221 7727 4.84 %RANDOM
Rwork0.185 ---
obs0.187 159596 97.8 %-
Displacement parametersBiso mean: 46.28 Å2
Baniso -1Baniso -2Baniso -3
1--6.356 Å20 Å20.3141 Å2
2--6.2945 Å20 Å2
3---0.0614 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.17→137.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19661 0 75 1401 21137
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0120139HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0727170HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d7128SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes3425HARMONIC5
X-RAY DIFFRACTIONt_it20139HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion17.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion2615SEMIHARMONIC5
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_contact23751SEMIHARMONIC4
LS refinement shellResolution: 2.17→2.23 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2737 600 5.08 %
Rwork0.2224 11222 -
all0.2249 11822 -
obs--97.42 %

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