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- PDB-9j5x: Cryo-EM Structure of URAT1 in Complex with Lingolinurad -

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Basic information

Entry
Database: PDB / ID: 9j5x
TitleCryo-EM Structure of URAT1 in Complex with Lingolinurad
ComponentsSolute carrier family 22 member 12
KeywordsMEMBRANE PROTEIN / Inhibitor / complex
Function / homology
Function and homology information


Organic anion transport by SLC22 transporters / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus ...Organic anion transport by SLC22 transporters / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus / apical plasma membrane / response to xenobiotic stimulus / membrane / 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 12
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsFan, J. / Lei, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: JACS Au / Year: 2025
Title: Structural Basis for Inhibition of Urate Reabsorption in URAT1.
Authors: Junping Fan / Wenjun Xie / Han Ke / Jing Zhang / Jin Wang / Haijun Wang / Nianxin Guo / Yingjie Bai / Xiaoguang Lei /
Abstract: The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common ...The urate transporter 1 (URAT1) is the primary urate transporter in the kidney responsible for urate reabsorption and, therefore, is crucial for urate homeostasis. Hyperuricemia causes the common human disease gout and other pathological consequences. Inhibition of urate reabsorption through URAT1 has been shown as a promising strategy in alleviating hyperuricemia, and clinical and preclinical drug candidates targeting URAT1 are emerging. However, how small molecules inhibit URAT1 remains undefined, and the lack of accurate URAT1 complex structures hinders the development of better therapeutics. Here, we present cryoelectron microscopy structures of a humanized rat URAT1 bound with benzbromarone, lingdolinurad, and verinurad, elucidating the structural basis for drug recognition and inhibition. The three small molecules reside in the URAT1 central cavity with different binding modes, locking URAT1 in an inward-facing conformation. This study provides mechanistic insights into the drug modulation of URAT1 and sheds light on the rational design of potential URAT1-specific therapeutics for treating hyperuricemia.
History
DepositionAug 13, 2024Deposition site: PDBJ / Processing site: PDBC
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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)60,6032
Polymers60,2331
Non-polymers3701
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 / Urate anion exchanger 1 / URAT1 / Urate:anion antiporter SLC22A12


Mass: 60233.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Slc22a12, Urat1 / Production host: Homo sapiens (human) / References: UniProt: Q3ZAV1
#2: Chemical ChemComp-A1EAP / 3-bromanyl-5-(2-ethylimidazo[1,2-a]pyridin-3-yl)carbonyl-2-oxidanyl-benzenecarbonitrile / Lingdolinurad


Mass: 370.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12BrN3O2 / 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 URAT1 in Complex with Lingolinurad
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88684 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034029
ELECTRON MICROSCOPYf_angle_d0.5745505
ELECTRON MICROSCOPYf_dihedral_angle_d5.738556
ELECTRON MICROSCOPYf_chiral_restr0.039649
ELECTRON MICROSCOPYf_plane_restr0.006691

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