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- EMDB-24656: Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide b... -

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Basic information

Entry
Database: EMDB / ID: EMD-24656
TitleCryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide bound outward open conformation
Map dataNanodisc reconstituted and nucleotide bound human ABCD1 (OO conformation)
Sample
  • Complex: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs
    • Protein or peptide: ATP-binding cassette sub-family D member 1
  • Ligand: UNKNOWN LIGAND
  • Ligand: CHOLESTEROL
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
Function / homology
Function and homology information


ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / long-chain fatty acid catabolic process / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid metabolic process ...ABC-type fatty-acyl-CoA transporter activity / peroxisomal membrane transport / very long-chain fatty-acyl-CoA catabolic process / long-chain fatty acid catabolic process / positive regulation of unsaturated fatty acid biosynthetic process / Linoleic acid (LA) metabolism / Defective ABCD1 causes ALD / long-chain fatty acid import into peroxisome / very long-chain fatty acid catabolic process / alpha-linolenic acid metabolic process / alpha-linolenic acid (ALA) metabolism / regulation of fatty acid beta-oxidation / Beta-oxidation of very long chain fatty acids / Class I peroxisomal membrane protein import / very long-chain fatty acid metabolic process / sterol homeostasis / peroxisome organization / regulation of mitochondrial depolarization / ABC transporters in lipid homeostasis / fatty acyl-CoA hydrolase activity / myelin maintenance / regulation of cellular response to oxidative stress / Hydrolases; Acting on ester bonds; Thioester hydrolases / positive regulation of fatty acid beta-oxidation / regulation of oxidative phosphorylation / linoleic acid metabolic process / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / fatty acid elongation / peroxisomal membrane / long-chain fatty acid transmembrane transporter activity / fatty acid beta-oxidation / ATPase-coupled transmembrane transporter activity / negative regulation of cytokine production involved in inflammatory response / fatty acid homeostasis / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / ADP binding / mitochondrial membrane / peroxisome / protein heterodimerization activity / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / ATP hydrolysis activity / protein homodimerization activity / ATP binding / membrane / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Peroxysomal long chain fatty acyl transporter / ABC transporter transmembrane region 2 / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. ...Peroxysomal long chain fatty acyl transporter / ABC transporter transmembrane region 2 / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ATP-binding cassette sub-family D member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsAlam A / Le LTM / Thompson JR
Funding support United States, 2 items
OrganizationGrant numberCountry
Other private
Other private United States
CitationJournal: Commun Biol / Year: 2022
Title: Structures of the human peroxisomal fatty acid transporter ABCD1 in a lipid environment.
Authors: Le Thi My Le / James Robert Thompson / Phuoc Xuan Dang / Janarjan Bhandari / Amer Alam /
Abstract: The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, ...The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design.
History
DepositionAug 9, 2021-
Header (metadata) releaseJan 19, 2022-
Map releaseJan 19, 2022-
UpdateJan 19, 2022-
Current statusJan 19, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rr9
  • Surface level: 0.032
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24656.png

Downloads & links

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Map

FileDownload / File: emd_24656.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNanodisc reconstituted and nucleotide bound human ABCD1 (OO conformation)
Voxel sizeX=Y=Z: 0.895 Å
Density
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.032
Minimum - Maximum-0.09108259 - 0.164943
Average (Standard dev.)1.0715035e-05 (±0.0049018906)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 322.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8950.8950.895
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z322.200322.200322.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-0.0910.1650.000

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Supplemental data

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Sample components

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Entire : Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs

EntireName: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs
Components
  • Complex: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs
    • Protein or peptide: ATP-binding cassette sub-family D member 1
  • Ligand: UNKNOWN LIGAND
  • Ligand: CHOLESTEROL
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

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Supramolecule #1: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs

SupramoleculeName: Human ABCD1 in Porcine BPL/Ch/MSP1D1 nanodiscs / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular ...Details: Human ABCD1 recombinantly expressed in HEK293 TREX cell line and reconstituted in MSP1D1 nanodiscs comprising 4:1 mixture of Porcine Brain Polar Lipids:Cholesterol. The reported molecular weight of 0.0829 MDa is for the monomer. The assembly is a homodimer. The dimer was confirmed using SEC.
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightExperimental: 82.9 KDa

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Macromolecule #1: ATP-binding cassette sub-family D member 1

MacromoleculeName: ATP-binding cassette sub-family D member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: ec: 7.6.2.4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.040867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPVLSRPRPW RGNTLKRTAV LLALAAYGAH KVYPLVRQCL APARGLQAPA GEPTQEASGV AAAKAGMNRV FLQRLLWLLR LLFPRVLCR ETGLLALHSA ALVSRTFLSV YVARLDGRLA RCIVRKDPRA FGWQLLQWLL IALPATFVNS AIRYLEGQLA L SFRSRLVA ...String:
MPVLSRPRPW RGNTLKRTAV LLALAAYGAH KVYPLVRQCL APARGLQAPA GEPTQEASGV AAAKAGMNRV FLQRLLWLLR LLFPRVLCR ETGLLALHSA ALVSRTFLSV YVARLDGRLA RCIVRKDPRA FGWQLLQWLL IALPATFVNS AIRYLEGQLA L SFRSRLVA HAYRLYFSQQ TYYRVSNMDG RLRNPDQSLT EDVVAFAASV AHLYSNLTKP LLDVAVTSYT LLRAARSRGA GT AWPSAIA GLVVFLTANV LRAFSPKFGE LVAEEARRKG ELRYMHSRVV ANSEEIAFYG GHEVELALLQ RSYQDLASQI NLI LLERLW YVMLEQFLMK YVWSASGLLM VAVPIITATG YSESDAEAVK KAALEKKEEE LVSERTEAFT IARNLLTAAA DAIE RIMSS YKEVTELAGY TARVHEMFQV FEDVQRCHFK RPRELEDAQA GSGTIGRSGV RVEGPLKIRG QVVDVEQGII CENIP IVTP SGEVVVASLN IRVEEGMHLL ITGPNGCGKS SLFRILGGLW PTYGGVLYKP PPQRMFYIPQ RPYMSVGSLR DQVIYP DSV EDMQRKGYSE QDLEAILDVV HLHHILQREG GWEAMCDWKD VLSGGEKQRI GMARMFYHRP KYALLDECTS AVSIDVE GK IFQAAKDAGI ALLSITHRPS LWKYHTHLLQ FDGEGGWKFE KLDSAARLSL TEEKQRLEQQ LAGIPKMQRR LQELCQIL G EAVAPAHVPA PSPQGPGGLQ GAST

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Macromolecule #2: UNKNOWN LIGAND

MacromoleculeName: UNKNOWN LIGAND / type: ligand / ID: 2 / Number of copies: 2 / Formula: UNL
Molecular weightTheoretical: 734.039 Da
Chemical component information


ChemComp, No image

ChemComp-UNL:
Unknown ligand

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / type: ligand / ID: 5 / Number of copies: 2 / Formula: AGS
Molecular weightTheoretical: 523.247 Da
Chemical component information

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

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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

Concentration0.5 mg/mL
BufferpH: 7.5
Details: 25mM HEPES pH 7.5, 150mM NaCl, 5mM ATP gammaS, 10mM Magnesium Chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average exposure time: 60.0 sec. / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf
Startup modelType of model: EMDB MAP
EMDB ID:

9791

Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 1 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 37237

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Atomic model buiding 1

Initial modelPDB ID:

6jbj

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7rr9:
Cryo-EM Structure of Nanodisc reconstituted ABCD1 in nucleotide bound outward open conformation

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