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- PDB-9mr5: Cryo-EM structure of human OATP1C1 F240A mutant in complex with e... -

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Basic information

Entry
Database: PDB / ID: 9mr5
TitleCryo-EM structure of human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
ComponentsSolute carrier organic anion transporter family member 1C1
KeywordsTRANSPORT PROTEIN / SLC transporter / E1G
Function / homology
Function and homology information


positive regulation of thyroid hormone generation / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / organic anion transmembrane transporter activity / bile acid transmembrane transporter activity / bile acid and bile salt transport / transport across blood-brain barrier ...positive regulation of thyroid hormone generation / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / thyroid hormone transport / organic anion transmembrane transporter activity / bile acid transmembrane transporter activity / bile acid and bile salt transport / transport across blood-brain barrier / monoatomic ion transport / transmembrane transport / basolateral plasma membrane / plasma membrane
Similarity search - Function
Organic anion transporter polypeptide / Organic Anion Transporter Polypeptide (OATP) family / Kazal-type serine protease inhibitor domain / Kazal domain superfamily / Kazal domain / Kazal domain profile. / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
ESTRONE BETA-D-GLUCURONIDE / Solute carrier organic anion transporter family member 1C1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsGe, Y. / Yadav, G.P. / Jiang, J. / Huang, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM150878 United States
CitationJournal: Cell / Year: 2025
Title: Structural insights into brain thyroid hormone transport via MCT8 and OATP1C1.
Authors: Yunhui Ge / Tongyi Dou / Thu Uyen Nguyen / Gaya P Yadav / Theodore G Wensel / Jiansen Jiang / Pengxiang Huang /
Abstract: Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones ...Adequate delivery of thyroid hormones to the brain is crucial for normal neurological development. MCT8 and OATP1C1, two solute carrier (SLC) transporters, mediate the passage of thyroid hormones across the blood-brain barrier and into the central nervous system. Mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), an X-linked birth defect characterized by neurodevelopmental impairments and peripheral hyperthyroidism, whereas OATP1C1 deficiency is linked to brain hypometabolism and progressive neurodegeneration. Here, we report cryoelectron microscopy (cryo-EM) structures of MCT8 and OATP1C1 bound with the active thyroid hormone triiodothyronine (T3) and the prohormone thyroxine (T4) at 2.9 and 2.3 Å resolutions, respectively. Combined with functional studies, we elucidate their distinct thyroid hormone recognition and transport mechanisms and explain disease mutations. Although extracellular allosteric sites are not a common feature of SLC transporters, we identify one in OATP1C1. Collectively, these findings illuminate key aspects of thyroid hormone transport, a fundamental process in development and disease.
History
DepositionJan 7, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier organic anion transporter family member 1C1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,9102
Polymers82,4631
Non-polymers4461
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Solute carrier organic anion transporter family member 1C1 / Organic anion transporter 1C1 / OATP1C1 / Organic anion transporter F / OATP-F / Organic anion ...Organic anion transporter 1C1 / OATP1C1 / Organic anion transporter F / OATP-F / Organic anion transporter polypeptide-related protein 5 / OAT-RP-5 / OATP-RP5 / Organic anion-transporting polypeptide 14 / OATP-14 / Solute carrier family 21 member 14 / Thyroxine transporter


Mass: 82463.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLCO1C1, OATP14, OATP1C1, OATPF, SLC21A14 / Production host: Homo sapiens (human) / References: UniProt: Q9NYB5
#2: Chemical ChemComp-E3G / ESTRONE BETA-D-GLUCURONIDE


Mass: 446.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30O8 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: human OATP1C1 F240A mutant in complex with estrone 3-glucuronide
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50.83 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20_4459: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 52355 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 85.61 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00314333
ELECTRON MICROSCOPYf_angle_d0.64365879
ELECTRON MICROSCOPYf_chiral_restr0.0414677
ELECTRON MICROSCOPYf_plane_restr0.0056718
ELECTRON MICROSCOPYf_dihedral_angle_d5.1307609

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