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- PDB-7o9w: Encequidar-bound human P-glycoprotein in complex with UIC2-Fab -

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Basic information

Entry
Database: PDB / ID: 7o9w
TitleEncequidar-bound human P-glycoprotein in complex with UIC2-Fab
Components
  • Multidrug resistance protein 1
  • UIC2 Fab-fragment heavy chain
  • UIC2 Fab-fragment light chain
KeywordsTRANSPORT PROTEIN / ABCB1 / MDR1 / P-glycoprotein / nanodisc / encequidar
Function / homology
Function and homology information


positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / Abacavir transmembrane transport / ceramide translocation / external side of apical plasma membrane ...positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / Abacavir transmembrane transport / ceramide translocation / external side of apical plasma membrane / Atorvastatin ADME / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / transepithelial transport / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transmembrane transporter activity / ATPase-coupled transmembrane transporter activity / transport across blood-brain barrier / xenobiotic metabolic process / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / response to xenobiotic stimulus / apical plasma membrane / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Type 1 protein exporter / 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. ...Type 1 protein exporter / 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
Chem-V5Q / ATP-dependent translocase ABCB1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsNosol, K. / Locher, K.P.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_189111 Switzerland
CitationJournal: J Med Chem / Year: 2022
Title: Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.
Authors: Sameer Urgaonkar / Kamil Nosol / Ahmed M Said / Nader N Nasief / Yahao Bu / Kaspar P Locher / Johnson Y N Lau / Michael P Smolinski /
Abstract: Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral ...Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp. The structure guided us to prudently decorate the encequidar scaffold with CYP3A4 pharmacophores, leading to the identification of several analogues with dual potency against P-gp and CYP3A4. , dual P-gp and CYP3A4 inhibitor improved the oral absorption of docetaxel by 3-fold as compared to vehicle, while itself remained poorly absorbed.
History
DepositionApr 17, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 26, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

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  • Deposited structure unit
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  • EMDB-12765
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Multidrug resistance protein 1
B: UIC2 Fab-fragment light chain
C: UIC2 Fab-fragment heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,7135
Polymers190,3313
Non-polymers1,3812
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5650 Å2
ΔGint-38 kcal/mol
Surface area72400 Å2

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Components

#1: Protein Multidrug resistance protein 1 / ATP-binding cassette sub-family B member 1 / P-glycoprotein 1


Mass: 141628.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Production host: Homo sapiens (human)
References: UniProt: P08183, ABC-type xenobiotic transporter, P-type phospholipid transporter
#2: Antibody UIC2 Fab-fragment light chain


Mass: 24321.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody UIC2 Fab-fragment heavy chain


Mass: 24381.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-V5Q / ~{N}-[2-[2-[4-[2-(6,7-dimethoxy-3,4-dihydro-1~{H}-isoquinolin-2-yl)ethyl]phenyl]-1,2,3,4-tetrazol-5-yl]-4,5-dimethoxy-phenyl]-4-oxidanylidene-2,3-dihydrochromene-2-carboxamide


Mass: 690.744 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H38N6O7 / 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

Component
IDNameTypeEntity IDParent-IDSource
1Nanodisc reconstituted human P-glycoprotein in complex with UIC2-Fab and encequidarCOMPLEX#1-#30RECOMBINANT
2Multidrug resistance protein 1COMPLEX#11RECOMBINANT
3FabCOMPLEX#2-#31RECOMBINANT
Molecular weightValue: 0.24 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Buffer solutionpH: 7.4
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 / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79634 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412893
ELECTRON MICROSCOPYf_angle_d0.77817466
ELECTRON MICROSCOPYf_dihedral_angle_d23.3644650
ELECTRON MICROSCOPYf_chiral_restr0.0471980
ELECTRON MICROSCOPYf_plane_restr0.0052203

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