9B1O
Pyrazinoate bound human URAT1 in the inward-facing state (site3)
Summary for 9B1O
| Entry DOI | 10.2210/pdb9b1o/pdb |
| EMDB information | 44086 |
| Descriptor | Solute carrier family 22 member 12, 2-acetamido-2-deoxy-beta-D-glucopyranose, PYRAZINE-2-CARBOXYLIC ACID (3 entities in total) |
| Functional Keywords | slc transporter, slc22a family, uric acid, inward facing, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 59602.71 |
| Authors | |
| Primary citation | Dai, Y.,Lee, C.H. Transport mechanism and structural pharmacology of human urate transporter URAT1. Cell Res., 34:776-787, 2024 Cited by PubMed Abstract: Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics. PubMed: 39245778DOI: 10.1038/s41422-024-01023-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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