8wjg

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of human protein A

Structural highlights

8wjg is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

S22AC_HUMAN Hereditary renal hypouricemia. The disease is caused by variants affecting the gene represented in this entry.

Function

S22AC_HUMAN Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:12024214, PubMed:22194875, PubMed:35144162, PubMed:35462902). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:12024214, PubMed:22194875). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:12024214). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (PubMed:12024214). Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption (PubMed:21350910). Orotate transport is Cl(-)-dependent (PubMed:21350910).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30 degrees rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.

Structural basis for the transport and substrate selection of human urate transporter 1.,He J, Liu G, Kong F, Tan Q, Wang Z, Yang M, He Y, Jia X, Yan C, Wang C, Qian H Cell Rep. 2024 Aug 14;43(8):114628. doi: 10.1016/j.celrep.2024.114628. PMID:39146184^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002 May 23;417(6887):447-52. PMID:12024214 doi:10.1038/nature742
↑ Miura D, Anzai N, Jutabha P, Chanluang S, He X, Fukutomi T, Endou H. Human urate transporter 1 (hURAT1) mediates the transport of orotate. J Physiol Sci. 2011 May;61(3):253-7. PMID:21350910 doi:10.1007/s12576-011-0136-0
↑ Tasic V, Hynes AM, Kitamura K, Cheong HI, Lozanovski VJ, Gucev Z, Jutabha P, Anzai N, Sayer JA. Clinical and functional characterization of URAT1 variants. PLoS One. 2011;6(12):e28641. PMID:22194875 doi:10.1371/journal.pone.0028641
↑ Shinoda Y, Yamashiro T, Hosooka A, Yasujima T, Yuasa H. Functional characterization of human organic anion transporter 10 (OAT10/SLC22A13) as an orotate transporter. Drug Metab Pharmacokinet. 2022 Apr;43:100443. PMID:35144162 doi:10.1016/j.dmpk.2021.100443
↑ Toyoda Y, Kawamura Y, Nakayama A, Morimoto K, Shimizu S, Tanahashi Y, Tamura T, Kondo T, Kato Y, Ichida K, Suzuki H, Shinomiya N, Kobayashi Y, Takada T, Matsuo H. OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts. Front Pharmacol. 2022 Apr 6;13:842717. PMID:35462902 doi:10.3389/fphar.2022.842717
↑ He J, Liu G, Kong F, Tan Q, Wang Z, Yang M, He Y, Jia X, Yan C, Wang C, Qian H. Structural basis for the transport and substrate selection of human urate transporter 1. Cell Rep. 2024 Aug 14;43(8):114628. PMID:39146184 doi:10.1016/j.celrep.2024.114628

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8wjg"

Categories: Homo sapiens | Large Structures | He JJ | Qian HW

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8wjg is ON HOLD
+==Cryo-EM structure of human protein A==
+<StructureSection load='8wjg' size='340' side='right'caption='[[8wjg]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8wjg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8WJG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WJG FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8wjg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wjg OCA], [https://pdbe.org/8wjg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wjg RCSB], [https://www.ebi.ac.uk/pdbsum/8wjg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wjg ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/S22AC_HUMAN S22AC_HUMAN] Hereditary renal hypouricemia. The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/S22AC_HUMAN S22AC_HUMAN] Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:12024214, PubMed:22194875, PubMed:35144162, PubMed:35462902). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:12024214, PubMed:22194875). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:12024214). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (PubMed:12024214). Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption (PubMed:21350910). Orotate transport is Cl(-)-dependent (PubMed:21350910).<ref>PMID:12024214</ref> <ref>PMID:21350910</ref> <ref>PMID:22194875</ref> <ref>PMID:35144162</ref> <ref>PMID:35462902</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+High serum urate levels are the major risk factor for gout. URAT1, the primary transporter for urate absorption in the kidneys, is well known as an anti-hyperuricemia drug target. However, the clinical application of URAT1-targeted drugs is limited because of their low specificity and severe side effects. The lack of structural information impedes elucidation of the transport mechanism and the development of new drugs. Here, we present the cryoelectron microscopy (cryo-EM) structures of human URAT1(R477S), its complex with urate, and its closely related homolog OAT4. URAT1(R477S) and OAT4 exhibit major facilitator superfamily (MFS) folds with outward- and inward-open conformations, respectively. Structural comparison reveals a 30 degrees rotation between the N-terminal and C-terminal domains, supporting an alternating access mechanism. A conserved arginine (OAT4-Arg473/URAT1-Arg477) is found to be essential for chloride-mediated inhibition. The URAT1(R477S)-urate complex reveals the specificity of urate recognition. Taken together, our study promotes our understanding of the transport mechanism and substrate selection of URAT1.
-Authors:
+Structural basis for the transport and substrate selection of human urate transporter 1.,He J, Liu G, Kong F, Tan Q, Wang Z, Yang M, He Y, Jia X, Yan C, Wang C, Qian H Cell Rep. 2024 Aug 14;43(8):114628. doi: 10.1016/j.celrep.2024.114628. PMID:39146184<ref>PMID:39146184</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8wjg" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: He JJ]]
+[[Category: Qian HW]]

8wjg

From Proteopedia

Current revision

Cryo-EM structure of human protein A

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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