8gqu

From Proteopedia

(Difference between revisions)

Current revision

AK-42 inhibitor binding human ClC-2 TMD

Structural highlights

8gqu is a 2 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 3.5Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CLCN2_HUMAN Leukoencephalopathy with mild cerebellar ataxia and white matter edema;Familial hyperaldosteronism type II;Juvenile myoclonic epilepsy. Disease susceptibility is associated with variants affecting the gene represented in this entry. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Disease susceptibility is associated with variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

CLCN2_HUMAN Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. Involved in the regulation of aldosterone production. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated Ca2+ channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis (PubMed:29403011, PubMed:29403012).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 A resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.

Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.,Ma T, Wang L, Chai A, Liu C, Cui W, Yuan S, Wing Ngor Au S, Sun L, Zhang X, Zhang Z, Lu J, Gao Y, Wang P, Li Z, Liang Y, Vogel H, Wang YT, Wang D, Yan K, Zhang H Nat Commun. 2023 Jun 9;14(1):3424. doi: 10.1038/s41467-023-39218-6. PMID:37296152^[5]

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

References

↑ Niemeyer MI, Cid LP, Yusef YR, Briones R, Sepúlveda FV. Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons. J Physiol. 2009 Apr 1;587(Pt 7):1387-400. PMID:19153159 doi:10.1113/jphysiol.2008.167353
↑ Saint-Martin C, Gauvain G, Teodorescu G, Gourfinkel-An I, Fedirko E, Weber YG, Maljevic S, Ernst JP, Garcia-Olivares J, Fahlke C, Nabbout R, LeGuern E, Lerche H, Poncer JC, Depienne C. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum Mutat. 2009 Mar;30(3):397-405. PMID:19191339 doi:10.1002/humu.20876
↑ Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018 Mar;50(3):349-354. PMID:29403011 doi:10.1038/s41588-018-0048-5
↑ Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, Schwarzmayr T, Strom TM, Jentsch TJ, Zennaro MC. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet. 2018 Mar;50(3):355-361. PMID:29403012 doi:10.1038/s41588-018-0053-8
↑ Ma T, Wang L, Chai A, Liu C, Cui W, Yuan S, Wing Ngor Au S, Sun L, Zhang X, Zhang Z, Lu J, Gao Y, Wang P, Li Z, Liang Y, Vogel H, Wang YT, Wang D, Yan K, Zhang H. Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42. Nat Commun. 2023 Jun 9;14(1):3424. PMID:37296152 doi:10.1038/s41467-023-39218-6

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/8gqu"

Categories: Homo sapiens | Large Structures | Wang L

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8gqu is ON HOLD
+==AK-42 inhibitor binding human ClC-2 TMD==
+<StructureSection load='8gqu' size='340' side='right'caption='[[8gqu]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8gqu]] is a 2 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=8GQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GQU 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]] 3.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GH6:2-[[2,6-bis(chloranyl)-3-phenylmethoxy-phenyl]amino]pyridine-3-carboxylic+acid'>GH6</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=8gqu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gqu OCA], [https://pdbe.org/8gqu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gqu RCSB], [https://www.ebi.ac.uk/pdbsum/8gqu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gqu ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/CLCN2_HUMAN CLCN2_HUMAN] Leukoencephalopathy with mild cerebellar ataxia and white matter edema;Familial hyperaldosteronism type II;Juvenile myoclonic epilepsy. Disease susceptibility is associated with variants affecting the gene represented in this entry.  Disease susceptibility may be associated with variants affecting the gene represented in this entry.  Disease susceptibility is associated with variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/CLCN2_HUMAN CLCN2_HUMAN] Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. Involved in the regulation of aldosterone production. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated Ca2+ channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis (PubMed:29403011, PubMed:29403012).<ref>PMID:19153159</ref> <ref>PMID:19191339</ref> <ref>PMID:29403011</ref> <ref>PMID:29403012</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 A resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.
-Authors:
+Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.,Ma T, Wang L, Chai A, Liu C, Cui W, Yuan S, Wing Ngor Au S, Sun L, Zhang X, Zhang Z, Lu J, Gao Y, Wang P, Li Z, Liang Y, Vogel H, Wang YT, Wang D, Yan K, Zhang H Nat Commun. 2023 Jun 9;14(1):3424. doi: 10.1038/s41467-023-39218-6. PMID:37296152<ref>PMID:37296152</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 8gqu" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Wang L]]

8gqu

From Proteopedia

Current revision

AK-42 inhibitor binding human ClC-2 TMD

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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