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- PDB-8kci: ATP-bound hMRP5 outward-open -

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Basic information

Entry
Database: PDB / ID: 8kci
TitleATP-bound hMRP5 outward-open
ComponentsATP-binding cassette sub-family C member 5
KeywordsMEMBRANE PROTEIN / ATP-bound hMRP5 outward-open
Function / homology
Function and homology information


purine nucleotide transport / macromolecule transmembrane transporter activity / cGMP transport / carbohydrate derivative transmembrane transporter activity / Hyaluronan biosynthesis and export / folate transmembrane transport / purine nucleotide transmembrane transporter activity / cAMP transport / heme transmembrane transporter activity / glutathione transmembrane transport ...purine nucleotide transport / macromolecule transmembrane transporter activity / cGMP transport / carbohydrate derivative transmembrane transporter activity / Hyaluronan biosynthesis and export / folate transmembrane transport / purine nucleotide transmembrane transporter activity / cAMP transport / heme transmembrane transporter activity / glutathione transmembrane transport / glutathione transmembrane transporter activity / heme transmembrane transport / hyaluronan biosynthetic process / ATPase-coupled inorganic anion transmembrane transporter activity / xenobiotic transmembrane transport / organic anion transmembrane transporter activity / export across plasma membrane / ABC-type xenobiotic transporter / Paracetamol ADME / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / ABC-type xenobiotic transporter activity / Azathioprine ADME / xenobiotic transport / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / ABC-family proteins mediated transport / transmembrane transport / Golgi lumen / basolateral plasma membrane / endosome membrane / apical plasma membrane / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
: / ABC transporter transmembrane region / 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. ...: / ABC transporter transmembrane region / 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
ADENOSINE-5'-TRIPHOSPHATE / ATP-binding cassette sub-family C member 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.94 Å
AuthorsLiu, Z.M. / Huang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Nat Commun / Year: 2024
Title: Inhibition and transport mechanisms of the ABC transporter hMRP5.
Authors: Ying Huang / Chenyang Xue / Ruiqian Bu / Cang Wu / Jiachen Li / Jinqiu Zhang / Jinyu Chen / Zhaoying Shi / Yonglong Chen / Yong Wang / Zhongmin Liu /
Abstract: Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, ...Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.
History
DepositionAug 7, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-binding cassette sub-family C member 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)161,8795
Polymers160,8161
Non-polymers1,0634
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein ATP-binding cassette sub-family C member 5 / Multi-specific organic anion transporter C / MOAT-C / Multidrug resistance-associated protein 5 / ...Multi-specific organic anion transporter C / MOAT-C / Multidrug resistance-associated protein 5 / SMRP / pABC11


Mass: 160815.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: ATP-bound hMRP5 / Source: (gene. exp.) Homo sapiens (human) / Gene: ABCC5, MRP5 / Production host: Homo sapiens (human)
References: UniProt: O15440, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate, ABC-type xenobiotic transporter
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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

ComponentName: ATP-bound hMRP5 outward-open / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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 FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1397085 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0139695
ELECTRON MICROSCOPYf_angle_d1.16813127
ELECTRON MICROSCOPYf_dihedral_angle_d4.2961297
ELECTRON MICROSCOPYf_chiral_restr0.0381534
ELECTRON MICROSCOPYf_plane_restr0.0071628

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