8gz2

From Proteopedia

(Difference between revisions)

Revision as of 07:38, 8 March 2023

Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin

Structural highlights

8gz2 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.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SCN1B_HUMAN Dravet syndrome;Familial progressive cardiac conduction defect;Generalized epilepsy with febrile seizures-plus;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

SCN1B_HUMAN Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.^[1] Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.^[2]

Publication Abstract from PubMed

The sodium channel Na(V)1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na(V)1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na(V)1.6/beta1/beta2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na(V)1.6 inhibition by the blocker. The apo-form structure reveals two potential Na(+) binding sites within the selectivity filter, suggesting a possible mechanism for Na(+) selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na(+) binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na(V)1.6 structure, ion conductance, and inhibition.

Structure of human Na(V)1.6 channel reveals Na(+) selectivity and pore blockade by 4,9-anhydro-tetrodotoxin.,Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D Nat Commun. 2023 Feb 23;14(1):1030. doi: 10.1038/s41467-023-36766-9. PMID:36823201^[3]

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

References

↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
↑ Qin N, D'Andrea MR, Lubin ML, Shafaee N, Codd EE, Correa AM. Molecular cloning and functional expression of the human sodium channel beta1B subunit, a novel splicing variant of the beta1 subunit. Eur J Biochem. 2003 Dec;270(23):4762-70. PMID:14622265
↑ Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D. Structure of human Na(V)1.6 channel reveals Na(+) selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. Nat Commun. 2023 Feb 23;14(1):1030. PMID:36823201 doi:10.1038/s41467-023-36766-9

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/8gz2"

Categories: Homo sapiens | Large Structures | Jiang D | Li Y

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8gz2 is ON HOLD  until Paper Publication
+==Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin==
+<StructureSection load='8gz2' size='340' side='right'caption='[[8gz2]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8gz2]] 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=8GZ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GZ2 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=WMK:(1R,2S,3S,4R,5R,9S,11S,12S,14R)-7-amino-2,4,12-trihydroxy-2-(hydroxymethyl)-10,13,15-trioxa-6,8-diazapentacyclo[7.4.1.1~3,12~.0~5,11~.0~5,14~]pentadec-7-en-8-ium+(non-preferred+name)'>WMK</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=8gz2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gz2 OCA], [https://pdbe.org/8gz2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gz2 RCSB], [https://www.ebi.ac.uk/pdbsum/8gz2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gz2 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/SCN1B_HUMAN SCN1B_HUMAN] Dravet syndrome;Familial progressive cardiac conduction defect;Generalized epilepsy with febrile seizures-plus;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry.  The gene represented in this entry may be involved in disease pathogenesis.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/SCN1B_HUMAN SCN1B_HUMAN] Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.<ref>PMID:14622265</ref>   Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.<ref>PMID:14622265</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The sodium channel Na(V)1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na(V)1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na(V)1.6/beta1/beta2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na(V)1.6 inhibition by the blocker. The apo-form structure reveals two potential Na(+) binding sites within the selectivity filter, suggesting a possible mechanism for Na(+) selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na(+) binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na(V)1.6 structure, ion conductance, and inhibition.
-Authors:
+Structure of human Na(V)1.6 channel reveals Na(+) selectivity and pore blockade by 4,9-anhydro-tetrodotoxin.,Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D Nat Commun. 2023 Feb 23;14(1):1030. doi: 10.1038/s41467-023-36766-9. PMID:36823201<ref>PMID:36823201</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 8gz2" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Jiang D]]
+[[Category: Li Y]]

8gz2

From Proteopedia

Revision as of 07:38, 8 March 2023

Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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