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- PDB-7jr7: Cryo-EM structure of ABCG5/G8 in complex with Fab 2E10 and 11F4 -

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Basic information

Entry
Database: PDB / ID: 7jr7
TitleCryo-EM structure of ABCG5/G8 in complex with Fab 2E10 and 11F4
Components
  • (ATP-binding cassette sub-family G member ...) x 2
  • Fab 11F4 heavy chain
  • Fab 11F4 light chain
  • Fab 2E10 heavy chain
  • Fab 2E10 light chain
KeywordsTRANSLOCASE/IMMUNE SYSTEM / ABC transporter / Sterol / ATP hydrolysis / Pump / Fab / complex / Cholesterol / membrane protein / TRANSLOCASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


negative regulation of intestinal phytosterol absorption / negative regulation of intestinal cholesterol absorption / Defective ABCG8 causes GBD4 and sitosterolemia / Defective ABCG5 causes sitosterolemia / ABC transporters in lipid homeostasis / sterol transport / intestinal cholesterol absorption / phospholipid transport / cholesterol transfer activity / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate ...negative regulation of intestinal phytosterol absorption / negative regulation of intestinal cholesterol absorption / Defective ABCG8 causes GBD4 and sitosterolemia / Defective ABCG5 causes sitosterolemia / ABC transporters in lipid homeostasis / sterol transport / intestinal cholesterol absorption / phospholipid transport / cholesterol transfer activity / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / cholesterol efflux / triglyceride homeostasis / response to ionizing radiation / response to muscle activity / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to nutrient / ATP-binding cassette (ABC) transporter complex / cholesterol homeostasis / transmembrane transport / receptor complex / apical plasma membrane / response to xenobiotic stimulus / protein heterodimerization activity / ATP hydrolysis activity / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
ABC transporter family G domain / ABC-2 type transporter / : / ABC-2 type transporter / ABC-2 type transporter / 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. ...ABC transporter family G domain / ABC-2 type transporter / : / ABC-2 type transporter / ABC-2 type transporter / 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. / P-loop containing nucleotide triphosphate hydrolases / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
ATP-binding cassette sub-family G member 8 / ATP-binding cassette sub-family G member 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsHuang, C.S. / Yu, X. / Min, X. / Wang, Z. / Zhang, H.
CitationJournal: Commun Biol / Year: 2021
Title: Cryo-EM structure of ABCG5/G8 in complex with modulating antibodies.
Authors: Hanzhi Zhang / Ching-Shin Huang / Xinchao Yu / Jonas Lee / Amit Vaish / Qing Chen / Mingyue Zhou / Zhulun Wang / Xiaoshan Min /
Abstract: The heterodimer of ATP-binding cassette transporter ABCG5 and ABCG8 mediates the excretion of sterols from liver and intestine, playing a critical role in cholesterol homeostasis. Here, we present ...The heterodimer of ATP-binding cassette transporter ABCG5 and ABCG8 mediates the excretion of sterols from liver and intestine, playing a critical role in cholesterol homeostasis. Here, we present the cryo-EM structure of ABCG5/G8 in complex with the Fab fragments from two monoclonal antibodies at 3.3Å resolution. The high-resolution structure reveals a unique dimer interface between the nucleotide-binding domains (NBD) of opposing transporters, consisting of an ordered network of salt bridges between the conserved NPXDFXXD motif and serving as a pivot point that may be important for the transport cycle. While mAb 11F4 increases the ATPase activity potentially by stabilization of the NBD dimer formation, mAb 2E10 inhibits ATP hydrolysis, likely by restricting the relative movement between the RecA and helical domain of ABCG8 NBD. Our study not only provides insights into the structural elements important for the transport cycle but also reveals novel epitopes for potential therapeutic interventions.
History
DepositionAug 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1May 12, 2021Group: Database references / Category: citation / citation_author
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.pdbx_database_id_DOI / _citation.year / _citation_author.name
Revision 1.2Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
A: ATP-binding cassette sub-family G member 5
B: ATP-binding cassette sub-family G member 8
C: Fab 11F4 heavy chain
D: Fab 11F4 light chain
E: Fab 2E10 heavy chain
F: Fab 2E10 light chain


Theoretical massNumber of molelcules
Total (without water)243,1166
Polymers243,1166
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15420 Å2
ΔGint-84 kcal/mol
Surface area86080 Å2

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Components

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ATP-binding cassette sub-family G member ... , 2 types, 2 molecules AB

#1: Protein ATP-binding cassette sub-family G member 5 / Sterolin-1


Mass: 72578.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG5 / Production host: Komagataella pastoris (fungus)
References: UniProt: Q9H222, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#2: Protein ATP-binding cassette sub-family G member 8 / Sterolin-2


Mass: 75752.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCG8 / Production host: Komagataella pastoris (fungus)
References: UniProt: Q9H221, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate

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Antibody , 4 types, 4 molecules CDEF

#3: Antibody Fab 11F4 heavy chain


Mass: 24173.945 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody Fab 11F4 light chain


Mass: 23191.529 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody Fab 2E10 heavy chain


Mass: 24132.939 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#6: Antibody Fab 2E10 light chain


Mass: 23286.709 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Details

Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1ABCG5/G8 in complex with Fab 2E10 and 11F4COMPLEXall0MULTIPLE SOURCES
2ABCG5/G8COMPLEX#1-#21RECOMBINANT
3Fab 11F4COMPLEX#3-#41RECOMBINANT
4Fab 2E10COMPLEX#5-#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Komagataella pastoris (fungus)4922
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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 FIELD
Image recordingElectron dose: 47.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
4Gctf1.06CTF correction
7PHENIX1.14model fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
13PHENIX1.14model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 492931 / Symmetry type: POINT

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