Donnerstag, 20. Oktober 2016, 17:00 - 18:00 iCal

Guest Lecture by Sun-Jo LEE (WUSTL)




UZA 2, Hörsaal 6
Althanstraße 14, 1090 Wien


The Doctoral Program ION CHANNELS AND TRANSPORTERS AS MOLECULAR DRUG TARGETS („MolTag“) is pleased to invite you to the following lecture:



by Dr. Sun-Joo LEE, Postdoctoral Research Fellow,

Dept. of Cell Biology and Physiology; Washington University in St. Louis;


on: Thursday, October 20th; 17:00 ct

at: UZA II, Althanstraße 14, Hörsaal 6 (Pharma and Food Lecture Series)


Abstract: Classical Kir2 channels are constitutively active and strongly inward rectifying. They are abundantly expressed in skeletal and cardiac muscles and establish highly negative resting membrane potentials that are critical for maintenance of normal electrical control of the heart beat and movement. Kir2 channel gating is strongly regulated by membrane lipids. PIP2 appears to be an absolutely required agonist, but high sensitivity to PIP2 requires the synergistic presence of bulk anionic lipids (PL(-)s). Even though recent crystal structures of eukaryotic Kir channels have revealed a PIP2 binding site and potential conformational changes occurring upon channel gating, our understanding of the gating mechanism is far from being complete.

Utilizing computational modeling and _in vitro_ biochemical assays, we have identified a unique site for the synergistic PL(-) binding and discovered that tethering of cytoplasmic domain (CTD) to the membrane is likely the molecular mechanism for the synergy. To gain further evidence, a lipid-partitioning tryptophan at the PL(-) site was introduced so that the interaction of the site with the membrane (or detergent molecules) was preserved in detergent crystals. High-resolution X-ray crystal structures of the mutant with or without added PIP2 (2.8 and 2.0 Å, respectively), reveal tight tethering of the CTD to the transmembrane domain (TMD) in each condition. The results strongly support our gating model in which PL(-) site interactions with bulk anionic lipids pull the CTD toward the membrane, inducing the formation of the high affinity primary PIP2 site, explaining the positive allostery between PL(-) binding and PIP2 sensitivity of channel activity.

Our current effort to further elucidate Kir2 channel gating mechanisms encompasses structure determination of different functional states including open, inactivated, blocked states and the molecular mechanisms of cholesterol inhibition of Kir2 channels.



Doktoratskolleg Molecular Drug Targets


Susanne Menschik-Zunzer
Department of Pharmacology and Toxicology
DK Molecular Drug Targets
01 5277 55320,