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Structural Insights into the Atomistic Mechanisms of Uric Acid Recognition and Translocation of Human Urate Anion Transporter 1
Southern Medical University, Guangzhou, Guangdong, China.
Southern Medical University, Guangzhou, Guangdong, China.ORCID iD: 0000-0001-7790-8197
Number of Authors: 132020 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 5, no 51, p. 33421-33432Article in journal (Refereed) Published
Abstract [en]

Background: Human urate transporter 1 (hURAT1) is the most pivotal therapeutic target for treating hyperuricemia. However, the molecular interactions between uric acid and URAT1 are still unknown due to lack of structural details. Methods: In the present study, several methods (homology modeling, sequence alignment, docking, and mutagenesis) were used to explain the atomistic mechanisms of uric acid transport of hURAT1. Results: Residues W357-F365 in the TMD7 and P484-R487 in the TMD11 present in the hURAT1 have unique roles in both binding to the uric acid and causing subsequent structural changes. These residues, located in the transport tunnel, were found to be related to the structural changes, as demonstrated by the reduced V max values and an unaltered expression of protein level. In addition, W357, G361, T363, F365, and R487 residues may confer high affinity for binding to uric acid. An outward-open homology model of hURAT1 revealed a crucial role for these two domains in the conformational changes of hURAT1. F241 and H245 in TMD5, and R477 and R487 in TMD11 may confer high affinity for uric acid, and as the docking analysis suggests, they may also enhance the affinity for the inhibitors. R477 relation to the structural changes was demonstrated by the V max values of the mutants and the contribution of positive charge to the uric acid selectivity. Conclusions: W357-F365 in TMD7, P484-R487 in TMD11, and residues F241, H245, and R477 were found to be critical for the translocation and recognition of uric acid.

Place, publisher, year, edition, pages
2020. Vol. 5, no 51, p. 33421-33432
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Pharmaceutical Sciences
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URN: urn:nbn:se:hh:diva-48360DOI: 10.1021/acsomega.0c05360PubMedID: 33403304OAI: oai:DiVA.org:hh-48360DiVA, id: diva2:1702780
Available from: 2022-10-11 Created: 2022-10-11 Last updated: 2023-03-07Bibliographically approved

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Nandakumar, Kutty Selva

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