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- PDB-8wjh: Cryo-EM structure of OAT4 -

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Basic information

Entry
Database: PDB / ID: 8wjh
TitleCryo-EM structure of OAT4
ComponentsSolute carrier family 22 member 11
KeywordsTRANSPORT PROTEIN / SLC
Function / homology
Function and homology information


Organic anion transport / sodium-independent organic anion transmembrane transporter activity / prostaglandin transport / prostaglandin transmembrane transporter activity / urate metabolic process / organic anion transport / organic anion transmembrane transporter activity / solute:inorganic anion antiporter activity / monoatomic ion transport / basal plasma membrane ...Organic anion transport / sodium-independent organic anion transmembrane transporter activity / prostaglandin transport / prostaglandin transmembrane transporter activity / urate metabolic process / organic anion transport / organic anion transmembrane transporter activity / solute:inorganic anion antiporter activity / monoatomic ion transport / basal plasma membrane / apical plasma membrane / external side of plasma membrane / extracellular exosome / plasma membrane
Similarity search - Function
Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 22 member 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsQian, H.W. / He, J.J.
Funding support1items
OrganizationGrant numberCountry
Other privateKY9100000034
CitationJournal: Cell Rep / Year: 2024
Title: Structural basis for the transport and substrate selection of human urate transporter 1.
Authors: Jingjing He / Guoyun Liu / Fang Kong / Qiulong Tan / Zhenzhou Wang / Meng Yang / Yonglin He / Xiaoxiao Jia / Chuangye Yan / Chao Wang / Hongwu Qian /
Abstract: High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the ...High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30° rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.
History
DepositionSep 26, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Data collection / Database references / Structure summary
Category: em_admin / em_entity_assembly ...em_admin / em_entity_assembly / pdbx_database_related / struct
Item: _em_admin.last_update / _em_admin.title ..._em_admin.last_update / _em_admin.title / _em_entity_assembly.name / _pdbx_database_related.details / _struct.title
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5422
Polymers56,5061
Non-polymers351
Water00
1


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

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Components

#1: Protein Solute carrier family 22 member 11 / Organic anion transporter 4 / OAT4 / Organic anion:dicarboxylate exchanger OAT4


Mass: 56506.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A11, OAT4 / Production host: Homo sapiens (human) / References: UniProt: Q9NSA0
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl / 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: Cryo-EM structure of OAT4 / Type: CELL / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 460072 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043913
ELECTRON MICROSCOPYf_angle_d0.9795327
ELECTRON MICROSCOPYf_dihedral_angle_d4.88534
ELECTRON MICROSCOPYf_chiral_restr0.047629
ELECTRON MICROSCOPYf_plane_restr0.005662

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