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- EMDB-11014: Cryo-EM map of human dihydrolipoamide succinyltransferase catalyt... -

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Basic information

Entry
Database: EMDB / ID: EMD-11014
TitleCryo-EM map of human dihydrolipoamide succinyltransferase catalytic domain (DLST)
Map data
Sample
  • Complex: human dihydrolipoamide succinyltransferase (DLST)
    • Protein or peptide: human dihydrolipoamide succinyltransferase catalytic domain (DLST)
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.7 Å
AuthorsBailey HJ / Bezerra GA / Foster W / McCorvie TJ / Saez LD / Yue WW
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
DepositionMay 7, 2020-
Header (metadata) releaseNov 18, 2020-
Map releaseNov 18, 2020-
UpdateNov 18, 2020-
Current statusNov 18, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0233
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0233
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11014.png

Downloads & links

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Map

FileDownload / File: emd_11014.map.gz / Format: CCP4 / Size: 155.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 344 pix.
= 330.24 Å		0.96 Å/pix.
x 344 pix.
= 330.24 Å		0.96 Å/pix.
x 344 pix.
= 330.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0233 / Movie #1: 0.0233
Minimum - Maximum-0.062817045 - 0.09612747
Average (Standard dev.)0.00048205853 (±0.0045434227)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions344344344
Spacing344344344
CellA=B=C: 330.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.960.960.96
M x/y/z344344344
origin x/y/z0.0000.0000.000
length x/y/z330.240330.240330.240
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS344344344
D min/max/mean-0.0630.0960.000

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Supplemental data

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Sample components

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Entire : human dihydrolipoamide succinyltransferase (DLST)

EntireName: human dihydrolipoamide succinyltransferase (DLST)
Components
  • Complex: human dihydrolipoamide succinyltransferase (DLST)
    • Protein or peptide: human dihydrolipoamide succinyltransferase catalytic domain (DLST)

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Supramolecule #1: human dihydrolipoamide succinyltransferase (DLST)

SupramoleculeName: human dihydrolipoamide succinyltransferase (DLST) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 1.059 MDa

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Macromolecule #1: human dihydrolipoamide succinyltransferase catalytic domain (DLST)

MacromoleculeName: human dihydrolipoamide succinyltransferase catalytic domain (DLST)
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGHHHHHHSS GVDLGTENLY FQSMDDLVTV KTPAFAESVT EGDVRWEKAV GDTVAEDEVV CEIETDKTSV QVPSPANGVI EALLVPDGGK VEGGTPLFTL RKTGAAPAKA KPAEAPAAAA PKAEPTAAAV PPPAAPIPTQ MPPVPSPSQP PSGKPVSAVK PTVAPPLAEP ...String:
MGHHHHHHSS GVDLGTENLY FQSMDDLVTV KTPAFAESVT EGDVRWEKAV GDTVAEDEVV CEIETDKTSV QVPSPANGVI EALLVPDGGK VEGGTPLFTL RKTGAAPAKA KPAEAPAAAA PKAEPTAAAV PPPAAPIPTQ MPPVPSPSQP PSGKPVSAVK PTVAPPLAEP GAGKGLRSEH REKMNRMRQR IAQRLKEAQN TCAMLTTFNE IDMSNIQEMR ARHKEAFLKK HNLKLGFMSA FVKASAFALQ EQPVVNAVID DTTKEVVYRD YIDISVAVAT PRGLVVPVIR NVEAMNFADI ERTITELGEK ARKNELAIED MDGGTFTISN GGVFGSLFGT PIINPPQSAI LGMHGIFDRP VAIGGKVEVR PMMYVALTYD HRLIDGREAV TFLRKIKAAV EDPRVLLLDL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
20.0 mMHepes
150.0 mMNaCl
0.5 mMTCEP
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: OTHER / Number grids imaged: 1 / Number real images: 619 / Average exposure time: 1.0 sec. / Average electron dose: 32.52 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal magnification: 150000

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Image processing

Particle selectionNumber selected: 165739
CTF correctionSoftware - Name: CTFFIND
Final reconstructionApplied symmetry - Point group: O (octahedral) / Resolution.type: BY AUTHOR / Resolution: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 3356
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 1 / Avg.num./class: 33072 / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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