7pqu
Ligand-bound human Kv3.1 cryo-EM structure (Lu AG00563)
Structural highlights
DiseaseKCNC1_HUMAN Progressive myoclonic epilepsy type 7. The disease is caused by variants affecting the gene represented in this entry. FunctionKCNC1_HUMAN Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (PubMed:25401298). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2, and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons.[UniProtKB:P25122][1] Publication Abstract from PubMedKv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 A resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35 degrees . This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders. Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators.,Botte M, Huber S, Bucher D, Klint JK, Rodriguez D, Tagmose L, Chami M, Cheng R, Hennig M, Abdul Rahman W PNAS Nexus. 2022 Jun 16;1(3):pgac083. doi: 10.1093/pnasnexus/pgac083. eCollection , 2022 Jul. PMID:36741467[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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