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SUMMARY: How is electrical signal generated?  - Nieng Yan\, Shirley M. Til
 ghman Professor of Molecular Biology\, Princeton University\, USA
DTSTART:20201102T160000Z
DTEND:20201102T170000Z
UID:TALK151693@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:The voltage-gated sodium (Nav) channels are responsible for th
 e initiation and propagation of action potentials. Being associated with a
  variety of channelopathies\, they are targeted by multiple pharmaceutical
  drugs and natural toxins. We determined the crystal structure of a bacter
 ial Nav channel NavRh in a potentially inactivated state a few years ago\,
  which is a homotetramer in primary sequence but exhibits structural asymm
 etry. Employing the modern methods of cryo-EM\, we determined the near ato
 mic resolution structures of a Nav channel from American cockroach (design
 ated NavPaS) and from electric eel (designated EeNav1.4). Most recently\, 
 we have determined the cryo-EM structures of the human Nav channels\, Nav1
 .2\, Nav1.4\, and Nav1.7 in complex with distinct auxiliary subunits and t
 oxins.These structures reveal the folding principle and structural details
  of the single-chain eukaryotic Nav channels that are distinct from homote
 trameric voltage-gated ion channels. Unexpectedly\, the two structures wer
 e captured in drastically different states. Whereas the structure of NavPa
 S has a closed pore and the four VSDs in distinct conformations\, that of 
 EeNav1.4 and the human channels is open at the intracelluar gate with VSDs
  exhibiting similar “up”states. The most striking conformational diffe
 renc occurs to the III-IV linker\, which is essential for fast inactivatio
 n. Based on the structural features\, we suggest an allosteric blocking me
 chanism for fast inactivation of Nav channels by the IFM motif. Structural
  comparison of the conformationally distinct Nav channels provides importa
 nt insights into the electromechanical coupling mechanism of Nav channels 
 and offers the 3D template to map hundredes of disease mutations.\n\nJoin 
 Zoom meeting https://zoom.us/j/99696631826?pwd=ckxaelB5d0ltMHE1bEN2dUVlbzZ
 BZz09\n\nMeeting ID: 996 9663 1826\nPasscode: 744191
LOCATION:Webinar via Zoom
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