9OA8

Cryo-EM structure of KCa3.1/calmodulin channel in complex with NS309

Summary for 9OA8

• Entry DOI: 10.2210/pdb9oa8/pdb
• EMDB information: 70275
• Descriptor: Intermediate conductance calcium-activated potassium channel protein 4, Calmodulin-1, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: ion channel, intermediate conductance calcium-activated potassium channel, calmodulin binding protein, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 237840.97

Authors

Nam, Y.W.,Zhang, M. (deposition date: 2025-04-19, release date: 2025-06-18, Last modification date: 2025-10-01)

Primary citation

Zhang, M.,Nam, Y.W.,Ramanishka, A.,Xu, Y.,Yasuda, R.M.,Im, D.,Cui, M.,Chandy, G.,Wulff, H.
Structural basis for the subtype-selectivity of K Ca 2.2 channel activators.
Res Sq, 2025

PubMed Abstract: Small-conductance (K2.2) and intermediate-conductance (K3.1) Ca-activated K channels are gated by a Ca-calmodulin dependent mechanism. NS309 potentiates the activity of both K2.2 and K3.1, while rimtuzalcap selectively activates K2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of K2.2 channels bound with NS309 and rimtuzalcap, in addition to K3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K2.2. Calmodulin's N-lobes in the K2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin's Nlobes in the K3.1 structure are closer to each other and are constrained by the HC helices of K3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting K2.2 channels.

PubMed: 40470184
DOI: 10.21203/rs.3.rs-6568445/v1

Experimental method

ELECTRON MICROSCOPY (3.59 Å)