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- PDB-8vhe: Crystal Structure of Human IDH1 R132Q in Complex with NADPH-TCEP ... -

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Basic information

Entry
Database: PDB / ID: 8vhe
TitleCrystal Structure of Human IDH1 R132Q in Complex with NADPH-TCEP Adduct
ComponentsIsocitrate dehydrogenase [NADP] cytoplasmic
KeywordsOXIDOREDUCTASE
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 / NADP+ metabolic process / 2-oxoglutarate 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 / 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 / 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 / Isocitrate/isopropylmalate dehydrogenase, conserved site / Isocitrate and isopropylmalate dehydrogenases signature. / Isopropylmalate dehydrogenase-like domain / Isocitrate/isopropylmalate dehydrogenase / Isocitrate/isopropylmalate dehydrogenase
Similarity search - Domain/homology
: / THIOCYANATE ION / Isocitrate dehydrogenase [NADP] cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsMealka, M. / Sohl, C.D. / Huxford, T.
Funding support United States, 2items
OrganizationGrant numberCountry
American Cancer SocietyRSG-19-075-01-TBE United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 GM137773 United States
CitationJournal: Nat Commun / Year: 2024
Title: Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, ...Authors: Mealka, M. / Sierra, N.A. / Avellaneda Matteo, D. / Albekioni, E. / Khoury, R. / Mai, T. / Conley, B.M. / Coleman, N.J. / Sabo, K.A. / Komives, E.A. / Bobkov, A.A. / Cooksy, A.L. / Silletti, S. / Schiffer, J.M. / Huxford, T. / Sohl, C.D.
History
DepositionDec 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)199,28828
Polymers194,0004
Non-polymers5,28824
Water16,808933
1
A: Isocitrate dehydrogenase [NADP] cytoplasmic
B: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,75315
Polymers97,0002
Non-polymers2,75313
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11760 Å2
ΔGint-99 kcal/mol
Surface area33870 Å2
MethodPISA
2
C: Isocitrate dehydrogenase [NADP] cytoplasmic
D: Isocitrate dehydrogenase [NADP] cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,53513
Polymers97,0002
Non-polymers2,53511
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11210 Å2
ΔGint-103 kcal/mol
Surface area32280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.298, 107.348, 109.941
Angle α, β, γ (deg.)90.000, 99.190, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Isocitrate dehydrogenase [NADP] cytoplasmic / IDH / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / ...IDH / IDH1 / Cytosolic NADP-isocitrate dehydrogenase / IDPc / NADP(+)-specific ICDH / Oxalosuccinate decarboxylase


Mass: 48500.117 Da / Num. of mol.: 4 / Mutation: R132Q
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+)

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Non-polymers , 6 types, 957 molecules

#2: Chemical
ChemComp-A1AAX / 3,3',3''-({(4R)-1-[(2R,3R,4S,5R)-5-({[(S)-{[(S)-{[(2R,3R,4R,5R)-5-(6-amino-9H-purin-9-yl)-3-hydroxy-4-(phosphonooxy)oxolan-2-yl]methoxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}methyl)-3,4-dihydroxyoxolan-2-yl]-3-carbamoyl-1,4-dihydropyridin-4-yl}-lambda~5~-phosphanetriyl)tripropanoic acid


Mass: 995.606 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H45N7O23P4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CNS
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 933 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.15 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.4 / Details: 200 mM KSCN, 24% (w/v) PEG 6000, and 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.16→108.53 Å / Num. obs: 101627 / % possible obs: 98.01 % / Redundancy: 3 % / Biso Wilson estimate: 34.07 Å2 / CC1/2: 0.992 / Net I/σ(I): 13
Reflection shellResolution: 2.16→2.18 Å / Num. unique obs: 1247 / CC1/2: 0.835

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.16→108.53 Å / SU ML: 0.2405 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.3775
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2233 5063 4.98 %
Rwork0.1714 96564 -
obs0.174 101627 97.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.75 Å2
Refinement stepCycle: LAST / Resolution: 2.16→108.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13119 0 327 933 14379
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008213758
X-RAY DIFFRACTIONf_angle_d0.884418590
X-RAY DIFFRACTIONf_chiral_restr0.05361990
X-RAY DIFFRACTIONf_plane_restr0.00652360
X-RAY DIFFRACTIONf_dihedral_angle_d12.84981893
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.16-2.180.26761650.24412935X-RAY DIFFRACTION91.26
2.18-2.210.28681650.23063255X-RAY DIFFRACTION98.87
2.21-2.230.26571550.21453291X-RAY DIFFRACTION99.37
2.23-2.260.2521760.21023222X-RAY DIFFRACTION99.33
2.26-2.290.28491810.20533289X-RAY DIFFRACTION99.31
2.29-2.320.27691670.21223240X-RAY DIFFRACTION99.27
2.32-2.360.25811510.2083276X-RAY DIFFRACTION99.07
2.36-2.390.26861570.21433256X-RAY DIFFRACTION99.07
2.39-2.430.30131770.23233195X-RAY DIFFRACTION97.82
2.43-2.470.31361650.22613218X-RAY DIFFRACTION98.69
2.47-2.510.25121640.213205X-RAY DIFFRACTION97.29
2.51-2.560.26361830.19753242X-RAY DIFFRACTION97.94
2.56-2.610.28421790.19463213X-RAY DIFFRACTION99.38
2.61-2.660.24791620.19153270X-RAY DIFFRACTION99.22
2.66-2.720.2471720.18013259X-RAY DIFFRACTION98.99
2.72-2.780.25291760.18433243X-RAY DIFFRACTION99.04
2.78-2.850.23621890.19063213X-RAY DIFFRACTION98.95
2.85-2.930.26691710.20463244X-RAY DIFFRACTION98.99
2.93-3.010.25571620.19713282X-RAY DIFFRACTION98.4
3.01-3.110.26361450.18243245X-RAY DIFFRACTION98.52
3.11-3.220.23621680.18193236X-RAY DIFFRACTION98.15
3.22-3.350.2181770.17613221X-RAY DIFFRACTION97.78
3.35-3.50.21721780.17033211X-RAY DIFFRACTION97.39
3.5-3.690.21261900.16243126X-RAY DIFFRACTION95.67
3.69-3.920.1781790.14753187X-RAY DIFFRACTION97.45
3.92-4.220.18391640.13583238X-RAY DIFFRACTION97.42
4.22-4.650.18311550.12453212X-RAY DIFFRACTION96.67
4.65-5.320.17631710.13563171X-RAY DIFFRACTION95.81
5.32-6.70.2031690.15913185X-RAY DIFFRACTION95.69
6.7-108.530.18521500.14873184X-RAY DIFFRACTION93.36
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)
10.2688063847660.121515133244-0.4401210581560.10415451464-0.04015622194011.11025969189-0.2157518112640.000884283147467-0.1859213746910.112774419580.09504467655540.2715671761080.571776456956-0.700397789179-0.002617940416130.521269965844-0.152574421818-0.01397149177780.6301660193620.08502355132790.439759404884-46.2214501044-12.1596732455-13.195946148
20.524908460009-0.172408716736-0.179543945880.282747372397-0.1267269888180.379504386497-0.0061776827002-0.005667437122860.0445748538915-0.0925962798458-0.004988466113020.03225490924180.0705868451479-0.05148285076247.91155420935E-60.261185859278-0.00995548106145-0.02124387847130.216929615872-0.003846973215790.262058955872-19.5349035397-9.2773016454-22.7004905199
30.5478630302910.417116965102-0.2725413908820.5430876423980.03832677582920.4558125226920.0218573195468-0.1657101548170.1231477642070.1550352018070.02791214873620.0499322154089-0.0258714040296-0.372516916635-2.00724190499E-50.3137294485830.05451056950420.01026933570140.4891301347150.01553455121160.327322620526-40.21801133041.52575949607-5.60913193744
40.1243707034520.1211263510010.206471098096-0.005385313253740.03042748585490.01932380596440.02837767963550.04880311188630.0612297731828-0.0199996288613-0.106986757082-0.153435680513-0.0711357947160.167747038784-4.04519943319E-50.310006993405-0.0453507825206-0.008333783199760.4851969044390.009051630619050.35558838660122.8627261793-8.07923719106-3.03648223939
50.2968095330230.268225229846-0.1330840248180.218206519091-0.1815853252570.178024020936-0.0585840669945-0.0490813547494-0.0219646392698-0.1642196700850.0021260858903-0.0768347987448-0.0458990237170.1871375736339.53211589395E-60.2865320437230.01964517065690.006808487711510.40892190780.003221905138580.2970615983410.7032811197-15.5278686237-18.6127001324
60.2386839672070.0580746528224-0.2285142353450.139687816419-0.08623088789250.1304210635720.136888628543-0.2318437511830.0554339989599-0.0359061371672-0.064683140646-0.00284740793795-0.003985644299090.02250831238289.92041784206E-60.279431613991-0.005377695742990.01006908267070.341850763885-0.03306633210310.262227484437-4.42493992757-10.0594306942-3.61317305066
70.6271862573950.0388070447979-0.2264996706130.4843432832160.1438037116360.522931300203-0.0426387042623-0.16017323646-0.1058809295770.004338338546290.01072778347010.03039431658870.104061934422-0.0268008043319-1.98588430896E-60.2725603200120.01537349474080.01048198186840.2449832173440.02802300192910.260571990583-15.8628390691-25.1717254225-9.80130588533
80.6554716510410.1291637642540.06903925882530.523810415256-0.2824160938320.167515335440.0630762353347-0.154801711110.0063735800368-0.0394081910313-0.0557356721734-0.00560944465095-0.0003927062400630.110171661637-2.37300978516E-50.2366971181020.001947770284150.007851903932150.322291078075-0.01417023085240.2230105350682.3688680945-8.86700166325-6.93339835374
90.2206369587010.0566390107465-0.03597625877680.3421571000490.2990102729680.3393703582620.042055525982-0.3223252778050.152982731050.266270360715-0.0487861048496-0.0803466602975-0.1266815556230.259958231276-2.27158812771E-50.341438065867-0.07225876681930.01054530824730.44947108414-0.06066417853930.34351951750610.24318120443.812579047320.620944501115
101.14987885030.121484852385-0.3036112593220.9335268179440.1590791203740.98174292777-0.0430401400895-0.0877178088287-0.1176820065610.1607149966020.031846547278-0.0843205543840.2548831301080.0778841017138-1.5971989008E-50.3003051645770.03396849349-0.02075443649840.2173547701260.03159409278350.2755854741197.74605759564-24.187241930444.9136442006
110.6341214758290.398932783055-0.249509681090.266515606657-0.09709200140070.3775352128580.01587102603760.0005225850548340.1029151852430.05185825773330.03686340808490.06840120524970.01301508397320.1556499556571.46741248273E-50.286652294541-0.007664646154610.01697612928710.217445834334-0.004722269360110.273875205183-16.829568991-19.939041897255.3347427393
120.8514519175570.1698809992420.03798012550750.554237996596-0.2590803654240.339189067320.01497689801660.119807147557-0.00195134680066-0.059458480923-0.00913389060719-0.0768141547794-0.02185470281480.04017380893553.43526542762E-60.2566626482660.015015852782-0.003752335067490.2260105275340.0001450665064480.2581580127526.85136665506-18.147162023233.0412265978
130.2775887810040.03786894897-0.2011773346830.289136591194-0.003043556941190.218720239262-0.0677276041995-0.1567688066720.06223304631770.2021826953390.05789002210170.351870167901-0.169009985328-0.255127910712-7.53601420082E-50.3645965354790.01381351034950.02705053688490.3477627276980.02033200172360.518617938979-47.1610955875-24.333155238447.1137486375
140.5788676983970.2107882177450.110051361650.252639210823-0.0133534290330.548833400197-0.05461801029710.109133336273-0.02372195885080.02344129123190.0692341326650.09431564107810.043799787390.0778670043611-6.44646571071E-60.27502719675-0.000322040201290.01707500261360.246926463569-0.00425426491610.270550668101-23.8052058603-35.363830355344.7117679464
150.456370009084-0.332957363933-0.06836476543190.451653936208-0.1342261579220.71702705646-0.1170947169980.245312243590.131278820234-0.05685288198370.09715511493330.356343089134-0.147890215722-0.1017505582982.73838513373E-50.307086907171-0.0302328642193-0.1011799103580.3185876588260.07618475779120.470207644182-43.3342117547-18.647556454629.1723575575
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid -1 through 94 )AA-1 - 941 - 96
22chain 'A' and (resid 95 through 285 )AA95 - 28597 - 287
33chain 'A' and (resid 286 through 412 )AA286 - 412288 - 414
44chain 'B' and (resid -8 through 29 )BF-8 - 291 - 38
55chain 'B' and (resid 30 through 94 )BF30 - 9439 - 103
66chain 'B' and (resid 95 through 133 )BF95 - 133104 - 142
77chain 'B' and (resid 134 through 260 )BF134 - 260143 - 269
88chain 'B' and (resid 261 through 349 )BF261 - 349270 - 358
99chain 'B' and (resid 350 through 412 )BF350 - 412359 - 421
1010chain 'C' and (resid 0 through 133 )CL0 - 1331 - 134
1111chain 'C' and (resid 134 through 285 )CL134 - 285135 - 286
1212chain 'C' and (resid 286 through 413 )CL286 - 413287 - 414
1313chain 'D' and (resid 2 through 94 )DP2 - 941 - 93
1414chain 'D' and (resid 95 through 312 )DP95 - 31294 - 311
1515chain 'D' and (resid 313 through 412 )DP313 - 412312 - 411

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