8gz1

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (09:05, 4 June 2025) (edit) (undo)
 
Line 16: Line 16:
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.
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<ref>PMID:36823201</ref>
+
, PMID:36823201<ref>PMID:36823201</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Current revision

Cryo-EM structure of human NaV1.6/beta1/beta2,apo state

PDB ID 8gz1

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8gz1"
Personal tools