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- PDB-6sy1: Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1) -

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Basic information

Entry
Database: PDB / ID: 6sy1
TitleCrystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1)
ComponentsProbable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial
KeywordsSTRUCTURAL GENOMICS / Dehydrogenase / transketolase / thiamine pyrophosphate / Mg / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


Oxidoreductases; Acting on the aldehyde or oxo group of donors; With a disulfide as acceptor / oxoglutarate dehydrogenase (succinyl-transferring) activity / Glyoxylate metabolism and glycine degradation / thiamine pyrophosphate binding / hematopoietic progenitor cell differentiation / tricarboxylic acid cycle / generation of precursor metabolites and energy / glycolytic process / mitochondrial matrix / mitochondrion
Similarity search - Function
Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal domain / Rossmann fold - #12470 / Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal / Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal domain superfamily / 2-oxoglutarate dehydrogenase C-terminal / 2-oxoglutarate dehydrogenase E1 component / Dehydrogenase, E1 component / Dehydrogenase E1 component / Transketolase-like, pyrimidine-binding domain / Transketolase, pyrimidine binding domain ...Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal domain / Rossmann fold - #12470 / Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal / Multifunctional 2-oxoglutarate metabolism enzyme, C-terminal domain superfamily / 2-oxoglutarate dehydrogenase C-terminal / 2-oxoglutarate dehydrogenase E1 component / Dehydrogenase, E1 component / Dehydrogenase E1 component / Transketolase-like, pyrimidine-binding domain / Transketolase, pyrimidine binding domain / Transketolase, pyrimidine binding domain / Thiamin diphosphate (ThDP)-binding fold, Pyr/PP domains / Thiamin diphosphate-binding fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
THIAMINE DIPHOSPHATE / 2-oxoadipate dehydrogenase complex component E1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsBezerra, G.A. / Foster, W. / Shrestha, L. / Pena, I.A. / Coker, J. / Kolker, S. / Nicola, B.B. / von Delft, F. / Edwards, A. / Arrowsmith, C. ...Bezerra, G.A. / Foster, W. / Shrestha, L. / Pena, I.A. / Coker, J. / Kolker, S. / Nicola, B.B. / von Delft, F. / Edwards, A. / Arrowsmith, C. / Bountra, C. / Yue, W.W. / Structural Genomics Consortium (SGC)
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust092809/Z/10/Z United Kingdom
CitationJournal: IUCrJ / Year: 2020
Title: Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism.
Authors: Gustavo A Bezerra / William R Foster / Henry J Bailey / Kevin G Hicks / Sven W Sauer / Bianca Dimitrov / Thomas J McCorvie / Jürgen G Okun / Jared Rutter / Stefan Kölker / Wyatt W Yue /
Abstract: DHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid de-hydrogenases. In complex with E2 (di-hydro-lipo-amide succinyltransferase, DLST) and E3 (dihydrolipo-amide de-hydrogenase, DLD) ...DHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid de-hydrogenases. In complex with E2 (di-hydro-lipo-amide succinyltransferase, DLST) and E3 (dihydrolipo-amide de-hydrogenase, DLD) components, DHTKD1 is involved in lysine and tryptophan catabolism by catalysing the oxidative de-carboxyl-ation of 2-oxoadipate (2OA) in mitochondria. Here, the 1.9 Å resolution crystal structure of human DHTKD1 is solved in complex with the thi-amine diphosphate co-factor. The structure reveals how the DHTKD1 active site is modelled upon the well characterized homologue 2-oxoglutarate (2OG) de-hydrogenase but engineered specifically to accommodate its preference for the longer substrate of 2OA over 2OG. A 4.7 Å resolution reconstruction of the human DLST catalytic core is also generated by single-particle electron microscopy, revealing a 24-mer cubic scaffold for assembling DHTKD1 and DLD protomers into a megacomplex. It is further demonstrated that missense DHTKD1 variants causing the inborn error of 2-amino-adipic and 2-oxoadipic aciduria impact on the complex formation, either directly by disrupting the interaction with DLST, or indirectly through destabilizing the DHTKD1 protein. This study provides the starting framework for developing DHTKD1 modulators to probe the intricate mitochondrial energy metabolism.
History
DepositionSep 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
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 / _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 / _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
Revision 1.2Oct 28, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.3Aug 4, 2021Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.pdbx_collection_date
Revision 1.4Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_beamline

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial
B: Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,7767
Polymers201,8522
Non-polymers9245
Water19,2041066
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12530 Å2
ΔGint-74 kcal/mol
Surface area54540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.550, 81.220, 86.900
Angle α, β, γ (deg.)63.430, 76.960, 72.060
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial / Dehydrogenase E1 and transketolase domain-containing protein 1


Mass: 100926.102 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHTKD1, KIAA1630 / Production host: Escherichia coli (E. coli)
References: UniProt: Q96HY7, oxoglutarate dehydrogenase (succinyl-transferring)
#2: Chemical ChemComp-TPP / THIAMINE DIPHOSPHATE / Thiamine pyrophosphate


Mass: 425.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H19N4O7P2S
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1066 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.32 Å3/Da / Density % sol: 47.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 20% PEG3350 -- 10% ethylene glycol -- 0.1M bis-tris-propane pH 8.5 -- 0.2M sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 25, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.87→46.01 Å / Num. obs: 145107 / % possible obs: 96.6 % / Redundancy: 1.8 % / Biso Wilson estimate: 16.081 Å2 / Rpim(I) all: 0.102 / Rrim(I) all: 0.144 / Net I/σ(I): 5 / Num. measured all: 254605
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
1.87-1.91.50.91028668640.4750.67291.3
5.07-46.021.813.51321074410.0450.06398.9

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JGD

2jgd


Resolution: 1.87→46.006 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 25.29
RfactorNum. reflection% reflection
Rfree0.2296 7088 4.89 %
Rwork0.19 --
obs0.1919 144961 96.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 92.18 Å2 / Biso mean: 26.2993 Å2 / Biso min: 10.71 Å2
Refinement stepCycle: final / Resolution: 1.87→46.006 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13331 0 87 1066 14484
Biso mean--20.15 28.07 -
Num. residues----1720
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.87-1.89130.34932270.3156433591
1.8913-1.91350.33732390.2955435692
1.9135-1.93680.31562320.2824443093
1.9368-1.96140.27652150.2664452494
1.9614-1.98720.29352390.2548453996
1.9872-2.01440.28492300.2438460096
2.0144-2.04320.27412310.2509454296
2.0432-2.07370.31672450.2428456196
2.0737-2.10610.26992610.2336455096
2.1061-2.14060.26452420.2211460196
2.1406-2.17750.28332340.2132460396
2.1775-2.21710.2961910.2205461797
2.2171-2.25970.25422450.2148458096
2.2597-2.30590.27122570.203456896
2.3059-2.3560.26262530.2052461497
2.356-2.41080.26332520.1998458597
2.4108-2.47110.23722310.1951464397
2.4711-2.53790.26532420.2065464097
2.5379-2.61260.25412350.1933461397
2.6126-2.69690.24812290.1862466597
2.6969-2.79330.22672180.1852462797
2.7933-2.90510.24352370.1888464197
2.9051-3.03730.22832450.1915464297
3.0373-3.19740.22882230.1886462198
3.1974-3.39760.2142330.1811474498
3.3976-3.65990.18852280.1721465498
3.6599-4.0280.19062560.1541465598
4.028-4.61040.16622300.1355473099
4.6104-5.80680.18472540.1512469499
5.8068-460.16722340.1654469999

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