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- PDB-6bkx: Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modi... -

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Basic information

Entry
Database: PDB / ID: 6bkx
TitleNovel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd1
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 / peroxisome / tertiary granule lumen / 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-DWP / ISOCITRIC ACID / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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 / struct_conn_type
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.ptnr2_symmetry / _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.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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 / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)146,20012
Polymers144,4643
Non-polymers1,7369
Water26,5001471
1
C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules

C: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,4678
Polymers96,3092
Non-polymers1,1576
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area8090 Å2
ΔGint-63 kcal/mol
Surface area33190 Å2
MethodPISA
2
B: Isocitrate dehydrogenase [NADP] cytoplasmic
A: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,4678
Polymers96,3092
Non-polymers1,1576
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8140 Å2
ΔGint-63 kcal/mol
Surface area32850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.301, 274.911, 116.897
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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.: 3
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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-ICT / ISOCITRIC ACID


Mass: 192.124 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H8O7
#4: Chemical ChemComp-DWP / (6aS,7S,9R,10aS)-7,10a-dimethyl-8-oxo-2-(phenylamino)-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazoline-9-carbonitrile


Mass: 346.426 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H22N4O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1471 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.72 Å3/Da / Density % sol: 54.77 %
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 7.4 / Details: 20% PEG 3350, 0.2M Potassium/Sodium tartrate

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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: Jul 8, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.65→137.46 Å / Num. obs: 184054 / % possible obs: 100 % / Redundancy: 6.7 % / Biso Wilson estimate: 24.02 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 15.2
Reflection shellResolution: 1.65→1.654 Å / Redundancy: 6.8 % / Rmerge(I) obs: 1.144 / Mean I/σ(I) obs: 2 / Num. unique obs: 1787 / % possible all: 99.8

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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: 1.65→137.46 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.955 / SU R Cruickshank DPI: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.084 / SU Rfree Blow DPI: 0.08 / SU Rfree Cruickshank DPI: 0.077
RfactorNum. reflection% reflectionSelection details
Rfree0.187 9096 4.94 %RANDOM
Rwork0.165 ---
obs0.166 184013 99.9 %-
Displacement parametersBiso mean: 28.01 Å2
Baniso -1Baniso -2Baniso -3
1--4.1411 Å20 Å20 Å2
2--2.6051 Å20 Å2
3---1.536 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: 1 / Resolution: 1.65→137.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9870 0 120 1472 11462
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110215HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0313787HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3607SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1750HARMONIC5
X-RAY DIFFRACTIONt_it10215HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.85
X-RAY DIFFRACTIONt_other_torsion16.35
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1330SEMIHARMONIC5
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_contact12878SEMIHARMONIC4
LS refinement shellResolution: 1.65→1.69 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2407 669 4.97 %
Rwork0.2131 12787 -
all0.2145 13456 -
obs--99.42 %

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