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- PDB-8wjq: Cryo-EM structure of URAT1(R477S)-Urate complex -

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Basic information

Entry
Database: PDB / ID: 8wjq
TitleCryo-EM structure of URAT1(R477S)-Urate complex
ComponentsSolute carrier family 22 member 12
KeywordsTRANSPORT PROTEIN / SLC
Function / homology
Function and homology information


Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / urate transport / renal urate salt excretion / urate transmembrane transporter activity / urate metabolic process / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding ...Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / urate transport / renal urate salt excretion / urate transmembrane transporter activity / urate metabolic process / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus / response to xenobiotic stimulus / apical plasma membrane / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
URIC ACID / Solute carrier family 22 member 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 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 / entity_name_com / pdbx_database_related / struct
Item: _em_admin.last_update / _em_admin.title ..._em_admin.last_update / _em_admin.title / _em_entity_assembly.name / _entity_name_com.name / _pdbx_database_related.details / _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,1962
Polymers58,0281
Non-polymers1681
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Solute carrier family 22 member 12 / Organic anion transporter 4-like protein / Renal-specific transporter / RST / Urate anion exchanger ...Organic anion transporter 4-like protein / Renal-specific transporter / RST / Urate anion exchanger 1 / URAT1 / Urate:anion antiporter SLC22A12 / URAT1-urate


Mass: 58027.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A12, OATL4, URAT1, UNQ6453/PRO34004 / Production host: Homo sapiens (human) / References: UniProt: Q96S37
#2: Chemical ChemComp-URC / URIC ACID / 7,9-DIHYDRO-1H-PURINE-2,6,8(3H)-TRIONE


Mass: 168.110 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H4N4O3 / 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: Cryo-EM structure of URAT1(R477S)-Urate complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
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: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 392817 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0094099
ELECTRON MICROSCOPYf_angle_d1.4485601
ELECTRON MICROSCOPYf_dihedral_angle_d5.087561
ELECTRON MICROSCOPYf_chiral_restr0.066661
ELECTRON MICROSCOPYf_plane_restr0.018697

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