Tyhe next NIH sponsored Joint CryoEM Service Centers Webinar Series “Structural basis for the pharmacological modulation of KCa2.2 channels” by Dr. Miao Zhang on Thursday April 30th, 2026 at 12pm (Eastern Time) (see attachment or below for details).
Miao Zhang, Ph.D.
Assistant Professor, Department of Basic Medical Sciences
College of Medicine-Phoenix, University of Arizona
12PM EDT / 9AM PDT Thursday, April 30th, 2026
Structural basis for the pharmacological modulation of KCa2.2 channels
Small-conductance (KCa2.2) and intermediate-conductance (KCa3.1) Ca2+-activated K+ channels are gated by a Ca2+-calmodulin dependent mechanism. We report cryo-electron microscopy structures of the KCa2.2 channel in complex with calmodulin and Ca2+. Extracellular S3-S4 loops in beta-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 beta-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter’s GYG signature by 180o, causing the outer selectivity filter to widen and water to enter the filter, which underlies the small unitary conductance of KCa2.2. NS309 potentiates the activity of both KCa2.2 and KCa3.1, while rimtuzalcap selectively activates KCa2.2. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for KCa2.2. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of KCa2.x channels.
All are welcome to attend. Registration is at no-cost, but sign-up is required:
