Chronic pain is an extremely common disease that affects about 20% people of general population. Given the shortage of effective and non-addictive analgesics, new anti-pain drugs are eagerly awaited. Voltage-gated sodium channel Na_V1.7 plays an essential role in the transmission of pain signals to the brain, many mutations in Na_V1.7 had been directly linked to a variety of human pain disorders. Blockade of Na_V1.7 can inhibit pain sensation, thus, it represents an attractive target for potential non-addictive analgesics. However, Na_V1.7 is a very challenging target for developing selective candidate drugs, partially owing to the high sequence similarity within the nine Na_V channel isoforms. 

Understanding the structural discriminations among Na_V channel isoforms and the mechanism of how these inhibitors regulate Na_V1.7 functions can support Na_V1.7-related drug development, ZHANG Jiangtao in Prof. JIANG Daohua's group from the Institute of Physics of the Chinese Academy of Sciences has reported the cryo-EM structures of Na_V1.7 in complex with three pore blockers, providing mechanistic insights into Na_V1.7 modulation by pore blockers.

The researchers solved high-resolution cryo-EM structures of Na_V1.7 complexed with three chemically distinct small molecule inhibitors XEN907, TCN-1752, and Na_V1.7-IN2, respectively.

The structure revealed the previously unresolved N-terminus domain (NTD) of Na_V1.7, explaining that the conserved NTD is critical for Na_V channel function.

In addition, the structures confirmed that the central cavity of Na_V1.7 accommodates multiple drug binding sites, which can directly block the channel. Two of the three inhibitors also caused local conformational rearrangements of the S6 helix, that further affect the channel function.

The XEN907 caused a α-helix to the π-helix transition in S6_IV of Na_V1.7, which significantly slowed down the recovery of Na_V1.7 from fast inactivation. The binding of TC-N1752 indirectly caused a local shift from the α-helix to the π-helix in S6_II of Na_V1.7, and shifted the S6_II helix approximately 5 Å toward the activation gate, leading to a completely closed activation gate, and stabilizing Na_V1.7 in the inactivated state.

Further structural analysis revealed that the inhibitor binding sites located in the central cavity are highly conserved among the nine Na_V channel isoforms. Therefore, it is very challenging to achieve subtype-selective drugs binding in the central cavity of Na_V channels.

This study suggests that future efforts on searching for Na_V1.7-selective inhibitors should focus on the regions that are relatively less conserved, such as the voltage-sensing domain.

This study entitled "Structural basis for Na_V1.7 inhibition by pore blockers" was published on Nature Structural & Molecular Biology.

The study was supported by the National Science Foundation of China, the Institute of Physics, and the Chinese Academy of Sciences.