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- PDB-9jdv: Human URAT1 bound with Uric acid -

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Basic information

Entry
Database: PDB / ID: 9jdv
TitleHuman URAT1 bound with Uric acid
ComponentsSolute carrier family 22 member 12
KeywordsTRANSPORT PROTEIN / URAT1
Function / homology
Function and homology information


Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding ...Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) / Organic anion transport / renal urate salt excretion / urate transport / urate metabolic process / urate transmembrane transporter activity / organic anion transport / cellular homeostasis / monoatomic ion transport / PDZ domain binding / brush border membrane / cellular response to insulin stimulus / apical plasma membrane / response to xenobiotic stimulus / 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: 3.32 Å
AuthorsWu, C. / Zhang, C. / Jin, S. / Wang, J.J. / Jiang, Y. / Yang, D. / Xu, H.E.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)32301016 China
Citation
Journal: Cell Discov / Year: 2025
Title: Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs.
Authors: Canrong Wu / Chao Zhang / Sanshan Jin / James Jiqi Wang / Antao Dai / Jiuyin Xu / Heng Zhang / Xuemei Yang / Xinheng He / Qingning Yuan / Wen Hu / Youwei Xu / Mingwei Wang / Yi Jiang / Dehua Yang / H Eric Xu /
Abstract: Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a ...Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Here, we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with urate in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout.
#1: Journal: Biorxiv / Year: 2024
Title: Molecular mechanisms of uric acid transport by the native human URAT1 and its inhibition by anti-gout drugs
Authors: Wu, C. / Zhang, C. / Jin, S. / Wang, J.J. / Dai, A. / Xu, J. / Zhang, H. / Yang, X. / He, X. / Yuan, Q. / Hu, W. / Xu, Y. / Wang, M. / Jiang, Y. / Yang, D. / Xu, H.E.
History
DepositionSep 1, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 2.0Oct 23, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Refinement description / Structure summary
Category: atom_site / audit_author ...atom_site / audit_author / em_admin / em_entity_assembly / em_imaging / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_close_contact / pdbx_validate_torsion / refine_ls_restr / struct_conf / struct_conn
Item: _em_admin.last_update / _em_entity_assembly.name ..._em_admin.last_update / _em_entity_assembly.name / _em_imaging.microscope_model / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.pdb_mon_id / _struct_conn.pdbx_dist_value
Description: Model completeness / Provider: author / Type: Coordinate replacement
Revision 2.1Oct 30, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 2.2Apr 16, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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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)59,8402
Polymers59,6721
Non-polymers1681
Water181
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


Mass: 59671.828 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
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 uric acid transporter 1 with uric acid / 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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON I (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82287 / Symmetry type: POINT

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