|Entry||Database: PDB / ID: 6gdi|
|Title||Structure of P-glycoprotein(ABCB1) in the post-hydrolytic state|
|Components||Multidrug resistance protein 1AMultiple drug resistance|
|Keywords||MEMBRANE PROTEIN / P-glycoprotein / ABCB1 / ATP-binding cassette / transporter / protein structure|
|Function / homology|
Function and homology information
terpenoid transport / establishment of blood-brain barrier / carbohydrate export / establishment of blood-retinal barrier / hormone transport / positive regulation of response to drug / daunorubicin transport / regulation of intestinal absorption / positive regulation of establishment of Sertoli cell barrier / carboxylic acid transmembrane transport ...terpenoid transport / establishment of blood-brain barrier / carbohydrate export / establishment of blood-retinal barrier / hormone transport / positive regulation of response to drug / daunorubicin transport / regulation of intestinal absorption / positive regulation of establishment of Sertoli cell barrier / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / ceramide floppase activity / ceramide translocation / positive regulation of anion channel activity / phosphatidylcholine floppase activity / floppase activity / phosphatidylethanolamine flippase activity / regulation of response to osmotic stress / xenobiotic transport across blood-brain barrier / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / stem cell proliferation / protein localization to bicellular tight junction / transepithelial transport / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / intercellular canaliculus / phospholipid translocation / intestinal absorption / xenobiotic transmembrane transporter activity / efflux transmembrane transporter activity / maintenance of blood-brain barrier / brush border membrane / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / negative regulation of cell death / regulation of chloride transport / transmembrane transport / apical part of cell / G2/M transition of mitotic cell cycle / apical plasma membrane / ATPase / ubiquitin protein ligase binding / cell surface / membrane / integral component of membrane / nucleoplasm / ATP binding / plasma membrane
ABC transporter transmembrane region / ABC transporter / Type 1 protein exporter / ABC transporter type 1, transmembrane domain superfamily / Multidrug resistance protein 1 / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ABC transporter-like
ATP-dependent translocase ABCB1
|Biological species||Mus musculus (house mouse)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.9 Å|
|Authors||Ford, R.C. / Thonghin, N. / Collins, R.F. / Barbieri, A. / Shafi, T. / Siebert, A.|
|Citation||Journal: BMC Struct Biol / Year: 2018|
Title: Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9 Å resolution.
Authors: Nopnithi Thonghin / Richard F Collins / Alessandro Barbieri / Talha Shafi / Alistair Siebert / Robert C Ford /
Abstract: BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. ...BACKGROUND: P-glycoprotein (ABCB1) is an ATP-binding cassette transporter that plays an important role in the clearance of drugs and xenobiotics and is associated with multi-drug resistance in cancer. Although several P-glycoprotein structures are available, these are either at low resolution, or represent mutated and/or quiescent states of the protein.
RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP ...RESULTS: In the post-hydrolytic state the structure of the wild-type protein has been resolved at about 8 Å resolution. The cytosolic nucleotide-binding domains (NBDs) are separated but ADP remains bound, especially at the first NBD. Gaps in the transmembrane domains (TMDs) that connect to an inner hydrophilic cavity are filled by density emerging from the annular detergent micelle. The NBD-TMD linker is partly resolved, being located between the NBDs and close to the Signature regions involved in cooperative NBD dimerization. This, and the gap-filling detergent suggest steric impediment to NBD dimerization in the post-hydrolytic state. Two central regions of density lie in two predicted drug-binding sites, implying that the protein may adventitiously bind hydrophobic substances even in the post-hydrolytic state. The previously unresolved N-terminal extension was observed, and the data suggests these 30 residues interact with the headgroup region of the lipid bilayer.
CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked ...CONCLUSION: The structural data imply that (i) a low basal ATPase activity is ensured by steric blockers of NBD dimerization and (ii) allocrite access to the central cavity may be structurally linked to NBD dimerization, giving insights into the mechanism of drug-stimulation of P-glycoprotein activity.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
Downloads & links
A: Multidrug resistance protein 1A
|#1: Protein|| |
Mass: 141877.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Abcb1a, Abcb4, Mdr1a, Mdr3, Pgy-3, Pgy3 / Production host: Komagataella pastoris (fungus) / References: UniProt: P21447, EC: 18.104.22.168
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: mouse P-glycoprotein / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Molecular weight||Experimental value: NO|
|Source (natural)||Organism: Mus musculus (house mouse)|
|Source (recombinant)||Organism: Komagataella pastoris (fungus)|
|Buffer solution||pH: 8|
|Specimen||Conc.: 1.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 295 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 7.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 135357 / Num. of class averages: 18 / Symmetry type: POINT|
|Atomic model building||Protocol: FLEXIBLE FIT|
|Atomic model building||PDB-ID: 4KSB|
Pdb chain-ID: a / Pdb chain residue range: 33-1271
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