8xdd

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of human urea transporter A2.

Structural highlights

8xdd is a 3 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
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UT2_HUMAN Mediates the transport of urea driven by a concentration gradient across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism.^[1] ^[2] Mediates the transport of urea driven by a concentration gradient across the cell membrane of the kidney inner medullary collecting duct which is critical to the urinary concentrating mechanism.^[3] ^[4]

Publication Abstract from PubMed

Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the Q(Pb)-T(5b)-T(5a)-Q(Pa) motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics.

Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters.,Huang SM, Huang ZZ, Liu L, Xiong MY, Zhang C, Cai BY, Wang MW, Cai K, Jia YL, Wang JL, Zhang MH, Xie YH, Li M, Zhang H, Weng CH, Wen X, Li Z, Sun Y, Yi F, Yang Z, Xiao P, Yang F, Yu X, Tie L, Yang BX, Sun JP Nat Commun. 2024 Nov 26;15(1):10226. doi: 10.1038/s41467-024-54305-y. PMID:39587082^[5]

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

References

↑ Bagnasco SM, Peng T, Janech MG, Karakashian A, Sands JM. Cloning and characterization of the human urea transporter UT-A1 and mapping of the human Slc14a2 gene. Am J Physiol Renal Physiol. 2001 Sep;281(3):F400-6. PMID:11502588 doi:10.1152/ajprenal.2001.281.3.F400
↑ Mistry AC, Mallick R, Fröhlich O, Klein JD, Rehm A, Chen G, Sands JM. The UT-A1 urea transporter interacts with snapin, a SNARE-associated protein. J Biol Chem. 2007 Oct 12;282(41):30097-106. PMID:17702749 doi:10.1074/jbc.M705866200
↑ Olivès B, Martial S, Mattei MG, Matassi G, Rousselet G, Ripoche P, Cartron JP, Bailly P. Molecular characterization of a new urea transporter in the human kidney. FEBS Lett. 1996 May 20;386(2-3):156-60. PMID:8647271 doi:10.1016/0014-5793(96)00425-5
↑ Martial S, Olivès B, Abrami L, Couriaud C, Bailly P, You G, Hediger MA, Cartron JP, Ripoche P, Rousselet G. Functional differentiation of the human red blood cell and kidney urea transporters. Am J Physiol. 1996 Dec;271(6 Pt 2):F1264-8. PMID:8997401 doi:10.1152/ajprenal.1996.271.6.F1264
↑ Huang SM, Huang ZZ, Liu L, Xiong MY, Zhang C, Cai BY, Wang MW, Cai K, Jia YL, Wang JL, Zhang MH, Xie YH, Li M, Zhang H, Weng CH, Wen X, Li Z, Sun Y, Yi F, Yang Z, Xiao P, Yang F, Yu X, Tie L, Yang BX, Sun JP. Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters. Nat Commun. 2024 Nov 26;15(1):10226. PMID:39587082 doi:10.1038/s41467-024-54305-y

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

Categories: Homo sapiens | Large Structures | Huang S | Liu L | Sun J

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8xdd is ON HOLD
+==Cryo-EM structure of human urea transporter A2.==
+<StructureSection load='8xdd' size='340' side='right'caption='[[8xdd]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8xdd]] is a 3 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=8XDD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XDD 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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8HC:8-HYDROXYQUINOLINE-2-CARBOXYLIC+ACID'>8HC</scene>, <scene name='pdbligand=SZ4:1-(3-METHOXYPHENYL)METHANAMINE'>SZ4</scene></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=8xdd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xdd OCA], [https://pdbe.org/8xdd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xdd RCSB], [https://www.ebi.ac.uk/pdbsum/8xdd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xdd ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/UT2_HUMAN UT2_HUMAN] Mediates the transport of urea driven by a concentration gradient across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism.<ref>PMID:11502588</ref> <ref>PMID:17702749</ref>   Mediates the transport of urea driven by a concentration gradient across the cell membrane of the kidney inner medullary collecting duct which is critical to the urinary concentrating mechanism.<ref>PMID:8647271</ref> <ref>PMID:8997401</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Urea's transmembrane transport through urea transporters (UT) is a fundamental physiological behavior for life activities. Here, we present 11 cryo-EM structures of four UT members in resting states, urea transport states, or inactive states bound with synthetic competitive, uncompetitive or noncompetitive inhibitor. Our results indicate that the binding of urea via a conserved urea recognition motif (URM) and the urea transport via H-bond transfer along the Q(Pb)-T(5b)-T(5a)-Q(Pa) motif among different UT members. Moreover, distinct binding modes of the competitive inhibitors 25a and ATB3, the uncompetitive inhibitor CF11 and the noncompetitive inhibitor HQA2 provide different mechanisms for blocking urea transport and achieved selectivity through L-P pocket, UCBP region and SCG pocket, respectively. In summary, our study not only allows structural understanding of urea transport via UTs but also afforded a structural landscape of hUT-A2 inhibition by competitive, uncompetitive and noncompetitive inhibitors, which may facilitate developing selective human UT-A inhibitors as a new class of salt-sparing diuretics.
-Authors: Shenming, H., Lei, L., Jinpeng, S.
+Structural insights into the mechanisms of urea permeation and distinct inhibition modes of urea transporters.,Huang SM, Huang ZZ, Liu L, Xiong MY, Zhang C, Cai BY, Wang MW, Cai K, Jia YL, Wang JL, Zhang MH, Xie YH, Li M, Zhang H, Weng CH, Wen X, Li Z, Sun Y, Yi F, Yang Z, Xiao P, Yang F, Yu X, Tie L, Yang BX, Sun JP Nat Commun. 2024 Nov 26;15(1):10226. doi: 10.1038/s41467-024-54305-y. PMID:39587082<ref>PMID:39587082</ref>
-Description: Cryo-EM structure of human urea transporter A2.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Shenming, H]]
+<div class="pdbe-citations 8xdd" style="background-color:#fffaf0;"></div>
-[[Category: Lei, L]]
+== References ==
-[[Category: Jinpeng, S]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang S]]
+[[Category: Liu L]]
+[[Category: Sun J]]

8xdd

From Proteopedia

Current revision

Cryo-EM structure of human urea transporter A2.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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