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- PDB-7yrq: Cryo-EM structure of human Peroxisomal ABC Transporter ABCD1 -

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Entry
Database: PDB / ID: 7yrq
TitleCryo-EM structure of human Peroxisomal ABC Transporter ABCD1
ComponentsATP-binding cassette sub-family D member 1
KeywordsSTRUCTURAL PROTEIN
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
Chem-K9G / ATP-binding cassette sub-family D member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsChao, X. / Li-Na, J. / Lin, T.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770897 China
National Natural Science Foundation of China (NSFC)81801294 China
CitationJournal: Signal Transduct Target Ther / Year: 2023
Title: Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.
Authors: Chao Xiong / Li-Na Jia / Wei-Xi Xiong / Xin-Tong Wu / Liu-Lin Xiong / Ting-Hua Wang / Dong Zhou / Zhen Hong / Zheng Liu / Lin Tang /
Abstract: Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome ...Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their β-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.
History
DepositionAug 10, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: ATP-binding cassette sub-family D member 1
B: ATP-binding cassette sub-family D member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,6044
Polymers166,0822
Non-polymers1,5222
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-binding cassette sub-family D member 1 / Adrenoleukodystrophy protein / ALDP


Mass: 83040.867 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCD1, ALD / Production host: Homo sapiens (human)
References: UniProt: P33897, Hydrolases; Acting on ester bonds; Thioester hydrolases, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#2: Chemical ChemComp-K9G / [(2~{R})-1-hexadecanoyloxy-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propan-2-yl] octadec-9-enoate


Mass: 761.084 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H83NO8P
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of human Peroxisomal ABC Transporter ABCD1
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 66.5 e/Å2 / Film or detector model: FEI EAGLE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 291703 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00710020
ELECTRON MICROSCOPYf_angle_d1.26213573
ELECTRON MICROSCOPYf_dihedral_angle_d29.5923647
ELECTRON MICROSCOPYf_chiral_restr0.0911524
ELECTRON MICROSCOPYf_plane_restr0.0061723

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