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Open data
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Basic information
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Title | Pendrin in complex with Niflumic acid | |||||||||
![]() | Pendrin in complex with Niflumic acid | |||||||||
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![]() | chloride transport / iodide transport / bicarbonate transport / TRANSPORT PROTEIN | |||||||||
Function / homology | ![]() iodide transmembrane transporter activity / secondary active sulfate transmembrane transporter activity / oxalate 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 | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
![]() | Wang L / Hoang A / Zhou M | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 28.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 16 KB 16 KB | Display Display | ![]() |
Images | ![]() | 63.6 KB | ||
Filedesc metadata | ![]() | 6.3 KB | ||
Others | ![]() ![]() | 27.9 MB 27.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8shcMC ![]() 8sgwC ![]() 8sh3C ![]() 8sieC ![]() 8uukC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Pendrin in complex with Niflumic acid | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.1 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half Map 1
File | emd_40483_half_map_1.map | ||||||||||||
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Annotation | Half Map 1 | ||||||||||||
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Density Histograms |
-Half map: Half Map 2
File | emd_40483_half_map_2.map | ||||||||||||
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Annotation | Half Map 2 | ||||||||||||
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Density Histograms |
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Sample components
-Entire : homodimer of Pendrin
Entire | Name: homodimer of Pendrin |
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Components |
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-Supramolecule #1: homodimer of Pendrin
Supramolecule | Name: homodimer of Pendrin / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 75 KDa |
-Macromolecule #1: Pendrin
Macromolecule | Name: Pendrin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 86.113273 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #2: CHLORIDE ION
Macromolecule | Name: CHLORIDE ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: CL |
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Molecular weight | Theoretical: 35.453 Da |
-Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
Macromolecule | Name: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 18 / Formula: LBN |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-LBN: |
-Macromolecule #4: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID
Macromolecule | Name: 2-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}NICOTINIC ACID / type: ligand / ID: 4 / Number of copies: 4 / Formula: NFL |
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Molecular weight | Theoretical: 282.218 Da |
Chemical component information | ![]() ChemComp-NFL: |
-Macromolecule #5: Lauryl Maltose Neopentyl Glycol
Macromolecule | Name: Lauryl Maltose Neopentyl Glycol / type: ligand / ID: 5 / Number of copies: 4 / Formula: AV0 |
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Molecular weight | Theoretical: 1.005188 KDa |
Chemical component information | ![]() ChemComp-AV0: |
-Macromolecule #6: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 12 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 10 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: INSILICO MODEL |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 437899 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |