7TJ9

Cryo-EM structure of the human Nax channel in complex with beta3 solved in GDN

Summary for 7TJ9

• Entry DOI: 10.2210/pdb7tj9/pdb
• EMDB information: 25919 25920
• Descriptor: Sodium channel protein type 7 subunit alpha, Sodium channel subunit beta-3, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: sodium channel, nav, ion channel, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 234368.40

Authors

Noland, C.L.,Kschonsak, M.,Ciferri, C.,Payandeh, J. (deposition date: 2022-01-14, release date: 2022-03-30, Last modification date: 2024-10-09)

Primary citation

Noland, C.L.,Chua, H.C.,Kschonsak, M.,Heusser, S.A.,Braun, N.,Chang, T.,Tam, C.,Tang, J.,Arthur, C.P.,Ciferri, C.,Pless, S.A.,Payandeh, J.
Structure-guided unlocking of Na X reveals a non-selective tetrodotoxin-sensitive cation channel.
Nat Commun, 13:1416-1416, 2022

PubMed Abstract: Unlike classical voltage-gated sodium (Na) channels, Na has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na)-activated channel involved in regulating Na homeostasis. However, Na remains refractory to functional characterization in traditional heterologous systems. Here, to gain insight into its atypical physiology, we determine structures of the human Na channel in complex with the auxiliary β3-subunit. Na reveals structural alterations within the selectivity filter, voltage sensor-like domains, and pore module. We do not identify an extracellular Na-sensor or any evidence for a Na-based activation mechanism in Na. Instead, the S6-gate remains closed, membrane lipids fill the central cavity, and the domain III-IV linker restricts S6-dilation. We use protein engineering to identify three pore-wetting mutations targeting the hydrophobic S6-gate that unlock a robust voltage-insensitive leak conductance. This constitutively active Na-QTT channel construct is non-selective among monovalent cations, inhibited by extracellular calcium, and sensitive to classical Na channel blockers, including tetrodotoxin. Our findings highlight a functional diversity across the Na channel scaffold, reshape our understanding of Na physiology, and provide a template to demystify recalcitrant ion channels.

PubMed: 35301303
DOI: 10.1038/s41467-022-28984-4

Experimental method

ELECTRON MICROSCOPY (2.9 Å)