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- EMDB-26807: Structure of the sodium/iodide symporter (NIS) in complex with pe... -

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Basic information

Entry
Database: EMDB / ID: EMD-26807
TitleStructure of the sodium/iodide symporter (NIS) in complex with perrhenate and sodium
Map dataSharpened map after local refinement.
Sample
  • Complex: Sodium/iodide symporter
    • Protein or peptide: Sodium/iodide cotransporter
  • Ligand: SODIUM ION
  • Ligand: PERRHENATE
  • Ligand: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE
KeywordsNIS / iodide / symporter / cryo-EM / TRANSPORT PROTEIN
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 / iodide transport / cellular response to gonadotropin stimulus / monoatomic anion transmembrane transport ...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 / iodide transport / cellular response to gonadotropin stimulus / monoatomic anion transmembrane transport / symporter activity / thyroid hormone generation / sodium ion transport / sodium ion transmembrane transport / cellular response to forskolin / cellular response to cAMP / 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: 3.2 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-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26807.png

Downloads & links

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Map

FileDownload / File: emd_26807.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map after local refinement.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 288 pix.
= 307.584 Å		1.07 Å/pix.
x 288 pix.
= 307.584 Å		1.07 Å/pix.
x 288 pix.
= 307.584 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.068 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-5.3496127 - 8.978
Average (Standard dev.)-0.0040550614 (±0.09497069)
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_26807_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Additional map: Unsharpened map after local refinement.

Fileemd_26807_additional_1.map
AnnotationUnsharpened map after local refinement.
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_26807_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_26807_half_map_2.map
Projections & Slices
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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: SODIUM ION
  • Ligand: PERRHENATE
  • 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 / Parent: 0 / Macromolecule list: #1 / Details: In complex with perrhenate and sodium.
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

UniProtKB: Sodium/iodide cotransporter

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Macromolecule #2: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 2 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #3: PERRHENATE

MacromoleculeName: PERRHENATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: REO
Molecular weightTheoretical: 250.205 Da
Chemical component information

ChemComp-REO:
PERRHENATE

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Macromolecule #4: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE

MacromoleculeName: 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / type: ligand / ID: 4 / Number of copies: 1 / Formula: 3PH
Molecular weightTheoretical: 704.998 Da
Chemical component information

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

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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 Chloride
75.0 mMTris-HCl
0.005 %LMNG
0.005 %GDN
1.0 mMSodium perrhenate
Sugar embeddingMaterial: vitrified ice
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsProtein was supplemented with 1 mM Sodium Perrhenate

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 2 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -0.00024 µm / Nominal defocus min: -0.00015 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 346284
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7uuz:
Structure of the sodium/iodide symporter (NIS) in complex with perrhenate and sodium

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