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- PDB-6i4q: Crystal structure of the human dihydrolipoamide dehydrogenase at ... -

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Basic information

Entry
Database: PDB / ID: 6i4q
TitleCrystal structure of the human dihydrolipoamide dehydrogenase at 1.75 Angstrom resolution
ComponentsDihydrolipoyl dehydrogenase, mitochondrial
KeywordsOXIDOREDUCTASE / Lipoamide dehydrogenase / Pathogenic mutation / E3 deficiency / Alpha-ketoglutarate dehydrogenase complex / 2-oxoglutarate dehydrogenase complex / Pyruvate dehydrogenase complex
Function / homology
Function and homology information


acetyltransferase complex / acrosomal matrix / OGDH complex synthesizes succinyl-CoA from 2-OG / OADH complex synthesizes glutaryl-CoA from 2-OA / oxoadipate dehydrogenase complex / Glycine degradation / branched-chain alpha-ketoacid dehydrogenase complex / BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV / Loss-of-function mutations in DBT cause MSUD2 / Loss-of-function mutations in DLD cause MSUD3/DLDD ...acetyltransferase complex / acrosomal matrix / OGDH complex synthesizes succinyl-CoA from 2-OG / OADH complex synthesizes glutaryl-CoA from 2-OA / oxoadipate dehydrogenase complex / Glycine degradation / branched-chain alpha-ketoacid dehydrogenase complex / BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV / Loss-of-function mutations in DBT cause MSUD2 / Loss-of-function mutations in DLD cause MSUD3/DLDD / H139Hfs13* PPM1K causes a mild variant of MSUD / PDH complex synthesizes acetyl-CoA from PYR / Branched-chain ketoacid dehydrogenase kinase deficiency / dihydrolipoyl dehydrogenase / dihydrolipoyl dehydrogenase (NADH) activity / Regulation of pyruvate dehydrogenase (PDH) complex / oxoglutarate dehydrogenase complex / pyruvate decarboxylation to acetyl-CoA / pyruvate dehydrogenase complex / branched-chain amino acid catabolic process / Branched-chain amino acid catabolism / 2-oxoglutarate metabolic process / pyruvate metabolic process / Signaling by Retinoic Acid / motile cilium / sperm capacitation / mitochondrial electron transport, NADH to ubiquinone / gastrulation / Mitochondrial protein degradation / regulation of membrane potential / flavin adenine dinucleotide binding / mitochondrial matrix / mitochondrion / proteolysis / nucleus
Similarity search - Function
Dihydrolipoamide dehydrogenase / : / Pyridine nucleotide-disulphide oxidoreductase, class I / FAD/NAD-linked reductase, C-terminal dimerisation domain / Pyridine nucleotide-disulphide oxidoreductase, class I, active site / Pyridine nucleotide-disulphide oxidoreductases class-I active site. / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / FAD/NAD-linked reductase, dimerisation domain superfamily / FAD/NAD(P)-binding domain ...Dihydrolipoamide dehydrogenase / : / Pyridine nucleotide-disulphide oxidoreductase, class I / FAD/NAD-linked reductase, C-terminal dimerisation domain / Pyridine nucleotide-disulphide oxidoreductase, class I, active site / Pyridine nucleotide-disulphide oxidoreductases class-I active site. / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / Pyridine nucleotide-disulphide oxidoreductase, dimerisation domain / FAD/NAD-linked reductase, dimerisation domain superfamily / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / Enolase-like; domain 1 / FAD/NAD(P)-binding domain / FAD/NAD(P)-binding domain / 3-Layer(bba) Sandwich / FAD/NAD(P)-binding domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / Dihydrolipoyl dehydrogenase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsNagy, B. / Szabo, E. / Wilk, P. / Torocsik, B. / Weiss, M.S. / Adam-Vizi, V. / Ambrus, A.
Funding support Hungary, United States, Germany, 10items
OrganizationGrant numberCountry
Hungarian Academy of Sciences02001 [to A.-V.V.] Hungary
Hungarian Scientific Research Fund, grant#112230 [to A.-V.V.] Hungary
Hungarian Brain Research Program, grant#KTIA_13_NAP_III/6 and 2017-1.2.1-NKP-2017-00002 [to A.-V.V.] Hungary
Hungarian Academy of SciencesBolyai Fellowship [to A.A.] Hungary
European Molecular Biology OrganizationShort-term Fellowship [to A.A.] Hungary
Semmelweis University, Young Investigator Research Grant [to A.A.] Hungary
Gedeon Richter PIc., Young Investigator Research Grant [to A.A.] Hungary
Fulbright Commission, Fulbright Fellowship [to A.A.] United States
European Union and Government of Hungary, grant#EFOP-3.6.3-VEKOP-16-2017-00009 [to S.E.] Hungary
European Union CALIPSOplus, grant#16204087-ST [to S.E. and A.A.] Germany
CitationJournal: Hum.Mol.Genet. / Year: 2019
Title: Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants.
Authors: Szabo, E. / Wilk, P. / Nagy, B. / Zambo, Z. / Bui, D. / Weichsel, A. / Arjunan, P. / Torocsik, B. / Hubert, A. / Furey, W. / Montfort, W.R. / Jordan, F. / Weiss, M.S. / Adam-Vizi, V. / Ambrus, A.
History
DepositionNov 10, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 24, 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydrolipoyl dehydrogenase, mitochondrial
B: Dihydrolipoyl dehydrogenase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,22516
Polymers105,2742
Non-polymers2,95014
Water9,674537
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, mass spectrometry, equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13440 Å2
ΔGint-166 kcal/mol
Surface area35700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)119.411, 169.945, 61.555
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A and segid A
21chain B and segid B

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and segid AA0
211chain B and segid BB0

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Components

#1: Protein Dihydrolipoyl dehydrogenase, mitochondrial / Dihydrolipoamide dehydrogenase / Glycine cleavage system L protein


Mass: 52637.172 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Sequence of the Strep-tag with linker amino-acids: MASWSHPQFEKGALEVLFQGPG
Source: (gene. exp.) Homo sapiens (human) / Gene: DLD, GCSL, LAD, PHE3 / Plasmid: pET52b+ / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P09622, dihydrolipoyl dehydrogenase
#2: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#3: Chemical ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 537 / 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: 3.07 Å3/Da / Density % sol: 59.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: 2 M ammonium sulfate, 1.5 (v/v)% PEG 400, 0.1 M Bis-Tris (pH 6.9)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.75→46.002 Å / Num. obs: 125138 / % possible obs: 98.1 % / Redundancy: 6.612 % / Biso Wilson estimate: 31.94 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Rrim(I) all: 0.096 / Χ2: 1.022 / Net I/σ(I): 10.72
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.75-1.856.4152.6940.55198370.6322.93197.4
1.85-1.986.8221.2751.31183870.8641.38195.6
1.98-2.146.6090.6512.42178940.9590.70799.9
2.14-2.346.5050.3224.95154840.9840.3594
2.34-2.626.860.1858.02149930.9950.299.9
2.62-3.026.5740.114.07132830.9980.108100
3.02-3.76.8230.05227.36112980.9990.05699.8
3.7-5.216.4030.03739.488370.9990.0499.7
5.21-46.0026.2240.03643.3851250.9990.03999.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.654
Highest resolutionLowest resolution
Rotation46 Å2.16 Å

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Processing

Software
NameVersionClassification
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ZMD

1zmd


Resolution: 1.75→46.002 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 32.74
Details: TLS groups, NCS torsion-angle restraints, automatic occupancy refinement and real-space refinement were involved, hydrogen atoms were added to the final model during refinement
RfactorNum. reflection% reflection
Rfree0.2238 2072 1.67 %
Rwork0.2052 --
obs0.2055 123930 97.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 255.5 Å2 / Biso mean: 54.3977 Å2 / Biso min: 24.97 Å2
Refinement stepCycle: final / Resolution: 1.75→46.002 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7077 0 284 537 7898
Biso mean--72.61 46.84 -
Num. residues----953
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087501
X-RAY DIFFRACTIONf_angle_d1.08910183
X-RAY DIFFRACTIONf_chiral_restr0.0431159
X-RAY DIFFRACTIONf_plane_restr0.0051295
X-RAY DIFFRACTIONf_dihedral_angle_d14.3062746
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A5116X-RAY DIFFRACTION7.968TORSIONAL
12B5116X-RAY DIFFRACTION7.968TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7476-1.78830.62231290.57717503763291
1.7883-1.8330.48881360.48318045818198
1.833-1.88260.40411400.39128248838899
1.8826-1.9380.48931220.47797326744889
1.938-2.00050.27281400.31478186832699
2.0005-2.0720.30071390.28478190832999
2.072-2.1550.26961390.26198246838599
2.155-2.25310.25591320.25987785791794
2.2531-2.37180.30531320.2757741787393
2.3718-2.52040.25931400.205782818421100
2.5204-2.7150.20861430.20238316845999
2.715-2.98820.23471430.20983548497100
2.9882-3.42050.23631440.194184288572100
3.4205-4.30890.16161440.14858431857599
4.3089-46.01790.15571490.139487788927100
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)
11.9110.78310.63772.9962-0.03330.95030.1121-0.07750.3090.35820.01250.60610.0427-0.2133-0.04260.37960.02170.16680.27390.02720.474928.94444.887422.9584
21.41170.51050.35473.0340.06361.347-0.096-0.09490.57560.05950.03760.4207-0.1631-0.21740.04140.3640.06190.11870.24260.04660.595333.990619.265616.7545
32.6761-1.07960.85922.2965-0.7942.12290.02580.57740.3843-1.23920.09370.40810.1724-0.1492-0.09540.6955-0.0855-0.07060.33370.12430.471327.5144.1658-3.5536
41.4430.81080.31133.0918-0.11760.7119-0.03270.1567-0.1199-0.2560.118-0.47990.03860.011-0.07750.3119-0.00360.14040.2326-0.02080.419346.4325-4.22311.9249
51.90820.45680.16695.12960.81252.5398-0.03140.4618-0.4209-1.08640.2753-0.02640.0510.0659-0.24380.6118-0.03740.00050.3684-0.12560.649142.886-45.44636.7791
65.9417-3.1325-1.84391.98230.20962.32080.07220.10840.0292-0.06370.16460.5280.0388-0.1862-0.1990.361-0.07240.0210.28430.04090.618524.0935-28.045418.1914
72.8465-1.3229-0.67774.92540.79450.63230.18670.3646-0.1608-0.6021-0.02510.9656-0.0463-0.3364-0.08680.5418-0.0647-0.14020.48340.13940.730619.5718-23.354112.7555
81.75160.2965-0.11183.56760.22652.24790.05160.2976-0.5293-0.38120.0304-0.34040.28760.211-0.10160.6079-0.00130.00170.3277-0.13030.751640.8308-51.633711.934
91.49511.771-0.57413.96-0.51282.26120.0838-0.1885-0.19330.53340.06020.7830.1224-0.2305-0.12850.4398-0.06310.08930.28860.07830.734518.44-34.628229.2327
105.78571.80330.22881.76460.53392.18410.1382-0.6687-0.05341.00120.07430.3029-0.13090.2952-0.1060.6387-0.06680.24310.23830.06290.506226.4892-23.114938.1039
112.01361.7237-1.85434.7285-0.30712.25140.2042-0.1614-0.14110.4330.08541.41390.0971-0.3794-0.30330.7171-0.09710.22330.40840.20680.836315.4252-35.873741.2316
122.76020.0084-0.54082.20150.00231.15430.059-0.3955-0.56290.36680.05430.5940.09450.02190.11910.5837-0.07060.07940.33480.14170.714824.2199-40.530635.132
132.181-0.5344-1.06143.94050.75762.49310.0343-0.2425-0.47260.51870.089-0.59290.62970.3534-0.11850.55020.0868-0.14110.3643-0.0060.77947.0485-46.070825.9737
14-0.01540.1935-0.19054.42351.08691.29270.1016-0.1409-0.32490.5010.2351-0.54150.11460.3014-0.26860.4594-0.015-0.03770.3231-0.04450.561545.1444-27.353327.4395
151.86480.494-0.68875.5386-0.3281.4630.1189-0.21050.02480.6913-0.0615-0.3826-0.06630.0541-0.04010.4204-0.02210.02470.2119-0.01850.370642.179-8.858129.3185
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 110 )A3 - 110
2X-RAY DIFFRACTION2chain 'A' and (resid 111 through 187 )A111 - 187
3X-RAY DIFFRACTION3chain 'A' and (resid 188 through 276 )A188 - 276
4X-RAY DIFFRACTION4chain 'A' and (resid 277 through 474 )A277 - 474
5X-RAY DIFFRACTION5chain 'B' and (resid -6 through 36 )B-6 - 36
6X-RAY DIFFRACTION6chain 'B' and (resid 37 through 67 )B37 - 67
7X-RAY DIFFRACTION7chain 'B' and (resid 68 through 109 )B68 - 109
8X-RAY DIFFRACTION8chain 'B' and (resid 110 through 152 )B110 - 152
9X-RAY DIFFRACTION9chain 'B' and (resid 153 through 199 )B153 - 199
10X-RAY DIFFRACTION10chain 'B' and (resid 200 through 233 )B200 - 233
11X-RAY DIFFRACTION11chain 'B' and (resid 234 through 260 )B234 - 260
12X-RAY DIFFRACTION12chain 'B' and (resid 261 through 288 )B261 - 288
13X-RAY DIFFRACTION13chain 'B' and (resid 289 through 327 )B289 - 327
14X-RAY DIFFRACTION14chain 'B' and (resid 328 through 380 )B328 - 380
15X-RAY DIFFRACTION15chain 'B' and (resid 381 through 474 )B381 - 474

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