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- EMDB-40483: Pendrin in complex with Niflumic acid -

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Basic information

Entry
Database: EMDB / ID: EMD-40483
TitlePendrin in complex with Niflumic acid
Map dataPendrin in complex with Niflumic acid
Sample
  • Organelle or cellular component: homodimer of Pendrin
    • Protein or peptide: Pendrin
  • Ligand: CHLORIDE IONChloride
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: CHOLESTEROL
Keywordschloride transport / iodide transport / bicarbonate transport / TRANSPORT PROTEIN
Function / homology
Function and homology information


iodide transmembrane transporter activity / secondary active sulfate transmembrane transporter activity / chloride:bicarbonate antiporter activity / regulation of pH / brush border membrane / regulation of protein localization / apical plasma membrane / extracellular exosome
Similarity search - Function
Sulphate anion transporter, conserved site / SLC26A transporters signature. / SLC26A/SulP transporter / SLC26A/SulP transporter domain / Sulfate permease family / STAS domain / STAS domain profile. / STAS domain / STAS domain superfamily
Similarity search - Domain/homology
Biological speciesSus scrofa (pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang L / Hoang A / Zhou M
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK122784 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM145416 United States
CitationJournal: Nat Commun / Year: 2024
Title: Mechanism of anion exchange and small-molecule inhibition of pendrin.
Authors: Lie Wang / Anthony Hoang / Eva Gil-Iturbe / Arthur Laganowsky / Matthias Quick / Ming Zhou /
Abstract: Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO) exchange for chloride (Cl) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin ...Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO) exchange for chloride (Cl) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl, I, HCO or in the apo-state. The structures reveal two anion-binding sites in each protomer, and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate Transporter and Anti-Sigma factor antagonist (STAS) and transmembrane domains, and mutational studies suggest a regulatory role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal directions for understanding the mechanisms of anion selectivity and exchange and their regulations by the STAS domain. This work also establishes a foundation for analyzing the pathophysiology of mutations associated with Pendred syndrome.
History
DepositionApr 13, 2023-
Header (metadata) releaseFeb 7, 2024-
Map releaseFeb 7, 2024-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40483.png

Downloads & links

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Map

FileDownload / File: emd_40483.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPendrin in complex with Niflumic acid
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 1.03
Minimum - Maximum-6.041368 - 8.194777500000001
Average (Standard dev.)0.04130701 (±0.26624438)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 220.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_40483_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_40483_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : homodimer of Pendrin

EntireName: homodimer of Pendrin
Components
  • Organelle or cellular component: homodimer of Pendrin
    • Protein or peptide: Pendrin
  • Ligand: CHLORIDE IONChloride
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID
  • Ligand: Lauryl Maltose Neopentyl Glycol
  • Ligand: CHOLESTEROL

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Supramolecule #1: homodimer of Pendrin

SupramoleculeName: homodimer of Pendrin / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 75 KDa

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Macromolecule #1: Pendrin

MacromoleculeName: Pendrin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 86.113273 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MAAPGSRLEP PPLPEYSCSY VVSRPVYSEL AFQQQYERRL QERKTLRESL AKRCSCSRKR TLGVLKTLLP VLDWLPKYRI KEWLLSDII SGVSTGLVGT LQGMAYALLA AVPVGYGLYS AFFPILTYFI FGTSRHISVG PFPVVSLMVG SVVLSMAPDE H FIISSSNG ...String:
MAAPGSRLEP PPLPEYSCSY VVSRPVYSEL AFQQQYERRL QERKTLRESL AKRCSCSRKR TLGVLKTLLP VLDWLPKYRI KEWLLSDII SGVSTGLVGT LQGMAYALLA AVPVGYGLYS AFFPILTYFI FGTSRHISVG PFPVVSLMVG SVVLSMAPDE H FIISSSNG TALNTTVIDF AARDAARVLI ASTLTLLVGI IQLIFGGLQI GFIVRYLADP LVGGFTTAAA FQVLVSQLKI VL NVSTKNY NGILSIIYTL IEIFQNIGNT NLADFIAGLL TIIICMAVKE LNDRFKHKIP VPIPIEVIVT IIATAISYAV NLE KNYNAG IVKSIPRGFL PPEIPPISLF SEMLTASFSI AVVAYAIAVS VGKVYAIKYD YTIDGNQEFI AFGISNIFSG FFSC FVATT ALSRTAVQES TGGKTQIAGI ISAAVVMIAI VALGKLLEPL QKSVLAAVVI ANLKGMFMQV CDVPRLWRQN KTDAV IWVF TCIASIILGL DLGLLAGLMF GFLTVVVRVQ FPSWNSLGSI PNTDIYRSTK DYKNIEEPEG VKILRFSSPI FYGNVD GLK KCIKSTVGFD AIRVYNKRLK ALRKIQKLIK KGQLRATKNG IISDAGSSNN AFEPDEDIED PEELDIPTKE IEIQVDW NS ELPVKVNVPK VPIHSLVLDC GAVSFLDVVG VRSLRMIVKE FQRIDVHVYF ASLQDHVIEK LEQCGFFNDS IRKDIFFL T VHDAILHLRS QVKSQEVQDS ILETITLIQD CKDPLELMEA ELIEEELDVQ DEAMRRLAS

UniProtKB: Pendrin

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Macromolecule #2: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 18 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM / POPC

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Macromolecule #4: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID

MacromoleculeName: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID / type: ligand / ID: 4 / Number of copies: 4 / Formula: NFL
Molecular weightTheoretical: 282.218 Da
Chemical component information

ChemComp-NFL:
2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID / inhibitor*YM / Niflumic acid

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Macromolecule #5: Lauryl Maltose Neopentyl Glycol

MacromoleculeName: Lauryl Maltose Neopentyl Glycol / type: ligand / ID: 5 / Number of copies: 4 / Formula: AV0
Molecular weightTheoretical: 1.005188 KDa
Chemical component information

ChemComp-AV0:
Lauryl Maltose Neopentyl Glycol

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 12 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 437899

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