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

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Entry
Database: PDB / ID: 7uuz
TitleStructure of the sodium/iodide symporter (NIS) in complex with perrhenate and sodium
ComponentsSodium/iodide cotransporter
KeywordsTRANSPORT PROTEIN / NIS / iodide / symporter / cryo-EM
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
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PERRHENATE / Sodium/iodide cotransporter
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsRavera, S. / Nicola, J.P. / Salazar-De Simone, G. / Sigworth, F. / Karakas, E. / Amzel, L.M. / Bianchet, M. / Carrasco, N.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium/iodide cotransporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,8934
Polymers73,9141
Non-polymers9783
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sodium/iodide cotransporter / Na(+)/I(-) cotransporter / Sodium-iodide symporter / Na(+)/I(-) symporter / Solute carrier family 5 member 5


Mass: 73914.414 Da / Num. of mol.: 1 / Mutation: N225Q, N485Q and N497Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Slc5a5, Nis / Production host: Homo sapiens (human) / References: UniProt: Q63008
#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-REO / PERRHENATE


Mass: 250.205 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: O4Re
#4: Chemical ChemComp-3PH / 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PHOSPHATIDIC ACID


Mass: 704.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H77O8P / 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

ComponentName: Sodium/iodide symporter / Type: COMPLEX / Details: In complex with perrhenate and sodium. / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.075 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human) / Cell: 293F
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1350 mMSodium ChlorideNaCl1
275 mMTris-HCl1
30.005 %LMNG1
40.005 %GDN1
51 mMSodium perrhenate1
SpecimenConc.: 2 mg/ml / Embedding applied: YES / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Protein was supplemented with 1 mM Sodium Perrhenate
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
EM embeddingMaterial: vitrified ice
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal magnification: 81000 X / Nominal defocus max: -0.24 nm / Nominal defocus min: -0.15 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 2

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
7Cootmodel fitting
9PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 346284 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL

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