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- PDB-6sy1: Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1) -
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Open data
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Basic information
Entry | Database: PDB / ID: 6sy1 | ||||||
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Title | Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1) | ||||||
![]() | Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial | ||||||
![]() | STRUCTURAL GENOMICS / Dehydrogenase / transketolase / thiamine pyrophosphate / Mg / Structural Genomics Consortium / SGC | ||||||
Function / homology | ![]() Oxidoreductases; Acting on the aldehyde or oxo group of donors; With a disulfide as acceptor / oxoglutarate dehydrogenase (succinyl-transferring) activity / oxoglutarate dehydrogenase complex / 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 ...Oxidoreductases; Acting on the aldehyde or oxo group of donors; With a disulfide as acceptor / oxoglutarate dehydrogenase (succinyl-transferring) activity / oxoglutarate dehydrogenase complex / 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 / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Bezerra, 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 | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 376.6 KB | Display | ![]() |
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PDB format | ![]() | 291.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 431 KB | Display | ![]() |
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Full document | ![]() | 450.7 KB | Display | |
Data in XML | ![]() | 69.7 KB | Display | |
Data in CIF | ![]() | 102.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 2jgdS S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Unit cell |
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Components
#1: Protein | Mass: 100926.102 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q96HY7, oxoglutarate dehydrogenase (succinyl-transferring) #2: Chemical | #3: Chemical | #4: Water | ChemComp-HOH / | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.32 Å3/Da / Density % sol: 47.09 % |
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Crystal grow | Temperature: 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 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||
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Diffraction source | Source: ![]() ![]() ![]() | ||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 25, 2018 | ||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | ||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.9762 Å / Relative weight: 1 | ||||||||||||||||||||||||
Reflection | Resolution: 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
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 2JGD Resolution: 1.87→46.006 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.96 / Phase error: 25.29
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 92.18 Å2 / Biso mean: 26.2993 Å2 / Biso min: 10.71 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.87→46.006 Å
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LS refinement shell | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0
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