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- EMDB-26806: Structure of the sodium/iodide symporter (NIS) -

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Basic information

Entry
Database: EMDB / ID: EMD-26806
TitleStructure of the sodium/iodide symporter (NIS)
Map dataSharpened map after local refinement.
Sample
  • Complex: Sodium/iodide symporter
    • Protein or peptide: Sodium/iodide cotransporter
  • Ligand: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE
Function / homology
Function and homology information


sodium:iodide symporter activity / iodide transmembrane transport / Thyroxine biosynthesis / cellular response to Thyroid stimulating hormone / Organic anion transporters / monoatomic anion:sodium symporter activity / iodide transmembrane transporter activity / cellular response to gonadotropin stimulus / iodide transport / symporter activity ...sodium:iodide symporter activity / iodide transmembrane transport / Thyroxine biosynthesis / cellular response to Thyroid stimulating hormone / Organic anion transporters / monoatomic anion:sodium symporter activity / iodide transmembrane transporter activity / cellular response to gonadotropin stimulus / iodide transport / symporter activity / thyroid hormone generation / sodium ion transport / cellular response to cAMP / cellular response to forskolin / transmembrane transport / protein homodimerization activity / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Sodium/iodide cotransporter / Sodium:solute symporter family signature 1. / Sodium/solute symporter, conserved site / Sodium/solute symporter / Sodium/glucose symporter superfamily / Sodium:solute symporter family / Sodium:solute symporter family profile.
Similarity search - Domain/homology
Sodium/iodide cotransporter
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsRavera S / Nicola JP / Salazar-De Simone G / Sigworth F / Karakas E / Amzel LM / Bianchet M / Carrasco N
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01-114250 United States
CitationJournal: Nature / Year: 2022
Title: Structural insights into the mechanism of the sodium/iodide symporter.
Authors: Silvia Ravera / Juan Pablo Nicola / Glicella Salazar-De Simone / Fred J Sigworth / Erkan Karakas / L Mario Amzel / Mario A Bianchet / Nancy Carrasco /
Abstract: The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones- ...The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones-the master regulators of intermediary metabolism. NIS couples the inward translocation of I against its electrochemical gradient to the inward transport of Na down its electrochemical gradient. For nearly 50 years before its molecular identification, NIS was the molecule at the centre of the single most effective internal radiation cancer therapy: radioiodide (I) treatment for thyroid cancer. Mutations in NIS cause congenital hypothyroidism, which must be treated immediately after birth to prevent stunted growth and cognitive deficiency. Here we report three structures of rat NIS, determined by single-particle cryo-electron microscopy: one with no substrates bound; one with two Na and one I bound; and one with one Na and the oxyanion perrhenate bound. Structural analyses, functional characterization and computational studies show the substrate-binding sites and key residues for transport activity. Our results yield insights into how NIS selects, couples and translocates anions-thereby establishing a framework for understanding NIS function-and how it transports different substrates with different stoichiometries and releases substrates from its substrate-binding cavity into the cytosol.
History
DepositionApr 29, 2022-
Header (metadata) releaseDec 21, 2022-
Map releaseDec 21, 2022-
UpdateJan 4, 2023-
Current statusJan 4, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26806.png

Downloads & links

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Map

FileDownload / File: emd_26806.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map after local refinement.
Voxel sizeX=Y=Z: 1.068 Å
Density
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-2.3871078 - 4.0693583
Average (Standard dev.)0.0026101968 (±0.062036637)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 307.58398 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26806_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map after local refinement

Fileemd_26806_additional_1.map
AnnotationUnsharpened map after local refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_26806_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26806_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Sodium/iodide symporter

EntireName: Sodium/iodide symporter
Components
  • Complex: Sodium/iodide symporter
    • Protein or peptide: Sodium/iodide cotransporter
  • Ligand: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE

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Supramolecule #1: Sodium/iodide symporter

SupramoleculeName: Sodium/iodide symporter / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 75 KDa

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Macromolecule #1: Sodium/iodide cotransporter

MacromoleculeName: Sodium/iodide cotransporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 73.914414 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MYPYDVPDYA ENLYFQSEGA EAGARATFGA WDYGVFATML LVSTGIGLWV GLARGGQRSA DDFFTGGRQL AAVPVGLSLA ASFMSAVQV LGVPAEAARY GLKFLWMCAG QLLNSLLTAF LFLPIFYRLG LTSTYQYLEL RFSRAVRLCG TLQYLVATML Y TGIVIYAP ...String:
MYPYDVPDYA ENLYFQSEGA EAGARATFGA WDYGVFATML LVSTGIGLWV GLARGGQRSA DDFFTGGRQL AAVPVGLSLA ASFMSAVQV LGVPAEAARY GLKFLWMCAG QLLNSLLTAF LFLPIFYRLG LTSTYQYLEL RFSRAVRLCG TLQYLVATML Y TGIVIYAP ALILNQVTGL DIWASLLSTG IICTLYTTVG GMKAVVWTDV FQVVVMLVGF WVILARGVIL LGGPRNVLSL AQ QHSRINL MDFDPDPRSR YTFWTFIVGG TLVWLSMYGV NQAQVQRYVA CHTEGKAKLA LLVNQLGLFL IVASAACCGI VMF VYYKDC DPLLTGRISA PDQYMPLLVL DIFEDLPGVP GLFLACAYSG TLSTASTSIN AMAAVTVEDL IKPRMPGLAP RKLV FISKG LSFIYGSACL TVAALSSLLG GGVLQGSFTV MGVISGPLLG AFTLGMLLPA CNTPGVLSGL AAGLAVSLWV AVGAT LYPP GEQTMGVLPT SAAGCTQDSV LLGPPGATQA SNGIPSSGMD TGRPALADTF YAISYLYYGA LGTLTTMLCG ALISYL TGP TKRSSLGPGL LWWDLARQTA SVAPKEDTAT LEESLVKGPE DIPAVTKKPP GLKPGAETHP LYLGHDVETN LSGGGGA LE VLFQGPHHHH HHHHMDEKTT GWRGGHVVEG LAGELEQLRA RLEHHPQGQR EP

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Macromolecule #2: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE

MacromoleculeName: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: 3PH
Molecular weightTheoretical: 704.998 Da
Chemical component information

ChemComp-3PH:
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / Phosphatidic acid

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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

Concentration2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
350.0 mMNaClSodium chlorideSodium Chloride
75.0 mMTris-HClTrisTris-HClTris
0.005 %LMNG
0.005 %GDN
Sugar embeddingMaterial: vitrified ice
GridModel: Quantifoil / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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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 / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 2 / Average electron dose: 45.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC
Details: Particles were symmetry expanded and local refinement was performed on one of the two protomers.
Number images used: 205030
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7uuy:
Structure of the sodium/iodide symporter (NIS)

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