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- PDB-7psc: Crystal structure of the disease-causing I358T mutant of the huma... -

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Basic information

Entry
Database: PDB / ID: 7psc
TitleCrystal structure of the disease-causing I358T mutant of the human dihydrolipoamide dehydrogenase
ComponentsDihydrolipoyl dehydrogenase, mitochondrialDihydrolipoamide dehydrogenase
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 / Glycine degradation / : / dihydrolipoyl dehydrogenase / dihydrolipoyl dehydrogenase activity / oxoglutarate dehydrogenase complex / acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase complex / : ...acetyltransferase complex / acrosomal matrix / Glycine degradation / : / dihydrolipoyl dehydrogenase / dihydrolipoyl dehydrogenase activity / oxoglutarate dehydrogenase complex / acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase complex / : / Lysine catabolism / branched-chain amino acid catabolic process / Citric acid cycle (TCA cycle) / Branched-chain amino acid catabolism / Pyruvate metabolism / Glyoxylate metabolism and glycine degradation / Regulation of pyruvate dehydrogenase (PDH) complex / motile cilium / sperm capacitation / Signaling by Retinoic Acid / mitochondrial electron transport, NADH to ubiquinone / Mitochondrial protein degradation / gastrulation / regulation of membrane potential / flavin adenine dinucleotide binding / mitochondrial matrix / mitochondrion / proteolysis / nucleus
Similarity search - Function
Dihydrolipoamide dehydrogenase / Pyridine nucleotide-disulphide oxidoreductase, class I / 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 / FAD/NAD(P)-binding domain superfamily
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: 2.436 Å
AuthorsNemes-Nikodem, E. / Szabo, E. / Zambo, Z. / Vass, K.R. / Taberman, H. / Torocsik, B. / Weiss, M.S. / Adam-Vizi, V. / Ambrus, A.
Funding support Hungary, European Union, 7items
OrganizationGrant numberCountry
Hungarian Academy of Sciences02001 [to A.-V.V.] Hungary
Hungarian National Research, Development and Innovation Office112230 [to A.-V.V.] Hungary
Hungarian Academy of SciencesKTIA_13_NAP_III/6 and 2017-1.2.1-NKP-2017-00002 [to A.-V.V.] Hungary
European Union (EU)Horizon 2020 Research and Innovation Programme, 16204087-ST [to S.E. and A.A.]European Union
Hungarian National Research, Development and Innovation OfficeFIKP 61826 690289 EATV [to A.A] Hungary
Hungarian National Research, Development and Innovation OfficeFIKP 61830Z0100 EATV [to A.A] Hungary
European Union (EU)Horizon 2020 Research and Innovation Programme MX-201-00149-ST [to A.A.]European Union
CitationJournal: Int J Mol Sci / Year: 2023
Title: Structural and Biochemical Investigation of Selected Pathogenic Mutants of the Human Dihydrolipoamide Dehydrogenase.
Authors: Szabo, E. / Nemes-Nikodem, E. / Vass, K.R. / Zambo, Z. / Zrupko, E. / Torocsik, B. / Ozohanics, O. / Nagy, B. / Ambrus, A.
History
DepositionSep 22, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 5, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2023Group: Author supporting evidence / Database references / Refinement description
Category: citation / citation_author ...citation / citation_author / pdbx_audit_support / struct_ncs_dom_lim
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_audit_support.country / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)107,6588
Polymers105,2502
Non-polymers2,4086
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12310 Å2
ΔGint-33 kcal/mol
Surface area34150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)188.960, 61.250, 85.010
Angle α, β, γ (deg.)90.000, 101.060, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 3 through 474 or resid 501 or resid 502 or resid 503))
21chain B

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLNGLNPHEPHE(chain A and (resid 3 through 474 or resid 501 or resid 502 or resid 503))AA3 - 47425 - 496
12FADFADFADFAD(chain A and (resid 3 through 474 or resid 501 or resid 502 or resid 503))AC501
13BTBBTBBTBBTB(chain A and (resid 3 through 474 or resid 501 or resid 502 or resid 503))AD502
14BTBBTBBTBBTB(chain A and (resid 3 through 474 or resid 501 or resid 502 or resid 503))AE503
21GLNGLNPHEPHEchain BBB3 - 47425 - 496

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Components

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


Mass: 52625.117 Da / Num. of mol.: 2 / Mutation: I358T
Source method: isolated from a genetically manipulated source
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 / Flavin adenine dinucleotide


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


Mass: 209.240 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O
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: 2.29 Å3/Da / Density % sol: 46.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.7
Details: 0.2 M magnesium chloride, 0.1 M BIS-TRIS (pH 6.7), 25 (v/v)% PEG 3350, 5 (v/v)% ethyl acetate

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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: Jan 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.436→49.118 Å / Num. obs: 35480 / % possible obs: 98.5 % / Redundancy: 6.786 % / Biso Wilson estimate: 84.895 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.082 / Rrim(I) all: 0.089 / Χ2: 0.78 / Net I/σ(I): 13.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.44-2.586.9864.1650.539200577156110.3624.49497.2
2.58-2.766.8981.9681.0737216544153950.6552.12699.2
2.76-2.986.7330.8912.333321501549490.8920.96598.7
2.98-3.266.9660.4334.7432429467846550.9750.46799.5
3.26-3.656.6540.1889.7527600423241480.9920.20398
3.65-4.216.9130.08619.9125648375737100.9990.09398.7
4.21-5.156.6030.04733.5420826319531540.9990.05198.7
5.15-7.246.4650.03742.1215879248724560.9990.04198.8
7.24-49.1186.1620.01775.7386391460140210.01996

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.611
Highest resolutionLowest resolution
Rotation49.12 Å3.34 Å

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Processing

Software
NameVersionClassification
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
MOLREP11.7.03; 13.07.2020phasing
PHENIX1.14refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6I4Q

6i4q


Resolution: 2.436→49.118 Å / SU ML: 0.63 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 47.17 / Stereochemistry target values: ML
Details: TLS groups and NCS torsion-angle restraints were included in refinement.
RfactorNum. reflection% reflection
Rfree0.2867 1768 5.01 %
Rwork0.2598 33544 -
obs0.2611 35312 98.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 233.63 Å2 / Biso mean: 131.9107 Å2 / Biso min: 71.48 Å2
Refinement stepCycle: final / Resolution: 2.436→49.118 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7025 0 162 11 7198
Biso mean--131.6 107.83 -
Num. residues----946
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4285X-RAY DIFFRACTION12.175TORSIONAL
12B4285X-RAY DIFFRACTION12.175TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.436-2.50170.65331280.7147243794
2.5017-2.57530.61811340.6369257298
2.5753-2.65840.5421350.5693257299
2.6584-2.75340.56321370.4754257998
2.7534-2.86360.53011330.4457252797
2.8636-2.9940.42571380.4302259699
2.994-3.15180.4041360.4076258799
3.1518-3.34920.38881370.3581258999
3.3492-3.60770.40591370.3207259898
3.6077-3.97060.33091360.2908258898
3.9706-4.54480.25351380.2148261199
4.5448-5.72460.23471380.1985262999
5.7246-49.10.16881410.1581265997
Refinement TLS params.Method: refined / Origin x: 32.4933 Å / Origin y: -32.9799 Å / Origin z: -38.0857 Å
111213212223313233
T0.8126 Å20.0531 Å2-0.0045 Å2-1.0578 Å2-0.0783 Å2--0.7334 Å2
L4.1444 °20.6364 °20.365 °2-1.4084 °20.3832 °2--1.3904 °2
S-0.3637 Å °-0.108 Å °-0.1388 Å °-0.1244 Å °0.3118 Å °-0.2324 Å °-0.0456 Å °0.839 Å °0.0288 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 474
2X-RAY DIFFRACTION1allA501
3X-RAY DIFFRACTION1allA502
4X-RAY DIFFRACTION1allA503
5X-RAY DIFFRACTION1allB3 - 474
6X-RAY DIFFRACTION1allB501
7X-RAY DIFFRACTION1allB502
8X-RAY DIFFRACTION1allB503
9X-RAY DIFFRACTION1allC1 - 11

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