Structural basis for Na_V1.7 inhibition by pore blockers

Area of Science:

• Structural biology
• Neuroscience
• Pharmacology

Background:

• Voltage-gated sodium channel Na_V1.7 is crucial for pain and odor perception.
• Na_V1.7 dysfunction is linked to pain disorders, making it a key target for analgesics.

Purpose of the Study:

• To elucidate the structural mechanisms of Na_V1.7 inhibition by specific pore blockers.
• To provide a structural basis for developing subtype-selective Na_V1.7 analgesics.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of human Na_V1.7/β1/β2 complexed with inhibitors.
• Electrophysiological studies were performed to assess the functional effects of the inhibitors.

Main Results:

• Cryo-EM structures revealed distinct binding sites for XEN907, TC-N1752, and Na_V1.7-IN2 within the central cavity of Na_V1.7.
• XEN907 and TC-N1752 induce conformational changes in key S6 helices, affecting channel gating and inactivation.
• Na_V1.7-IN2 acts as a pore blocker without inducing significant conformational changes.
• Electrophysiology confirmed that XEN907 and TC-N1752 stabilize the inactivated state and prolong recovery from inactivation.

Conclusions:

• The study provides detailed structural insights into how Na_V1.7 pore blockers function.
• These findings offer a structural framework for the rational design of novel, subtype-selective Na_V1.7 inhibitors for pain management.