{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Suo Y"],"funding":["Intramural NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood<sup>1</sup>. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population<sup>2-4</sup>. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout<sup>5</sup>. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown<sup>5</sup>. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the novel compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.09.11.612563"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11419087"],"repository":["biostudies-literature"],"pubmed_title":["Molecular basis of the urate transporter URAT1 inhibition by gout drugs."],"pmcid":["PMC11419087"],"funding_grant_id":["U24 GM129547","75N91019D00024","ZIC ES103326"],"pubmed_authors":["Zhan P","Tsolova K","Lee SY","Kumari S","Zhang H","Fedor JG","Im W","Sharma K","Suo Y","Shi X","Borgnia M"],"additional_accession":[]},"is_claimable":false,"name":"Molecular basis of the urate transporter URAT1 inhibition by gout drugs.","description":"Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood<sup>1</sup>. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population<sup>2-4</sup>. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout<sup>5</sup>. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown<sup>5</sup>. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the novel compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Sep","modification":"2026-04-21T03:30:40.431Z","creation":"2025-04-06T14:24:02.752Z"},"accession":"S-EPMC11419087","cross_references":{"pubmed":["39314352"],"doi":["10.1101/2024.09.11.612563"]}}