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SUMMARY:Keynote 9\,  Prof Nieng Yan: How is electrical signal generated?  
 Structural and mechanistic investigations of Nav channels
DTSTART;VALUE=DATE-TIME:20191011T070000Z
DTEND;VALUE=DATE-TIME:20191011T074000Z
DTSTAMP;VALUE=DATE-TIME:20260526T203233Z
UID:indico-contribution-770@lindico453.srv.lu.se
DESCRIPTION:Speakers: Nieng Yan (Princeton University\, USA)\nThe voltage-
 gated sodium (Nav) channels are responsible for the initiation and propaga
 tion of action potentials. Being associated with a variety of channelopath
 ies\, they are targeted by multiple pharmaceutical drugs and natural toxin
 s. We determined the crystal structure of a bacterial Nav channel NavRh in
  a potentially inactivated state a few years ago\, which is a homotetramer
  in primary sequence but exhibits structural asymmetry. Employing the mode
 rn methods of cryo-EM\, we determined the near atomic resolution structure
 s of a Nav channel from American cockroach (designated NavPaS) and from el
 ectric eel (designated EeNav1.4). Most recently\, we have determined the c
 ryo-EM structures of the human Nav channels\, Nav1.2\, Nav1.4\, and Nav1.7
  in complex with distinct auxiliary subunits and toxins.These structures r
 eveal the folding principle and structural details of the single-chain euk
 aryotic Nav channels that are distinct from homotetrameric voltage-gated i
 on channels. Unexpectedly\, the two structures were captured in drasticall
 y different states. Whereas the structure of NavPaS has a closed pore and 
 the four VSDs in distinct conformations\, that of EeNav1.4 and the human c
 hannels is open at the intracelluar gate with VSDs exhibiting similar “u
 p”states. The most striking conformational differenc occurs to the III-I
 V linker\, which is essential for fast inactivation. Based on the structur
 al features\, we suggest an allosteric blocking mechanism for fast inactiv
 ation of Nav channels by the IFM motif. Structural comparison of the confo
 rmationally distinct Nav channels provides important insights into the ele
 ctromechanical coupling mechanism of Nav channels and offers the 3D templa
 te to map hundredes of disease mutations.\n\nhttps://lindico453.srv.lu.se/
 event/125/contributions/770/
LOCATION:Kulturen Auditorium
URL:https://lindico453.srv.lu.se/event/125/contributions/770/
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