7XMG

Cryo-EM structure of human NaV1.7/beta1/beta2-TCN-1752

Summary for 7XMG

• Entry DOI: 10.2210/pdb7xmg/pdb
• EMDB information: 33296
• Descriptor: Isoform 3 of Sodium channel protein type 9 subunit alpha,Green fluorescent protein, Sodium channel subunit beta-1,Green fluorescent protein, Sodium channel subunit beta-2, ... (6 entities in total)
• Functional Keywords: sodium channel, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 336979.25

Authors

Jiang, D.H.,Zhang, J.T. (deposition date: 2022-04-25, release date: 2022-11-30, Last modification date: 2024-10-16)

Primary citation

Zhang, J.,Shi, Y.,Huang, Z.,Li, Y.,Yang, B.,Gong, J.,Jiang, D.
Structural basis for Na V 1.7 inhibition by pore blockers.
Nat.Struct.Mol.Biol., 29:1208-1216, 2022

PubMed Abstract: Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.

PubMed: 36424527
DOI: 10.1038/s41594-022-00860-1

Experimental method

ELECTRON MICROSCOPY (3.09 Å)