7PQU

Ligand-bound human Kv3.1 cryo-EM structure (Lu AG00563)

Summary for 7PQU

• Entry DOI: 10.2210/pdb7pqu/pdb
• Related: 7PQT
• EMDB information: 13604 13605
• Descriptor: Potassium voltage-gated channel subfamily C member 1, 1-(4-methylphenyl)sulfonyl-N-(1,3-oxazol-2-ylmethyl)pyrrole-3-carboxamide, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: potassium ion channel, voltage gated, drug target, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 237070.60

Authors

Botte, M.,Huber, S.,Bucher, D.,Klint, J.K.,Rodriguez, D.,Tagmose, L.,Chami, M.,Cheng, R.,Hennig, M.,Abdul Rhaman, W. (deposition date: 2021-09-20, release date: 2022-08-17, Last modification date: 2024-07-17)

Primary citation

Botte, M.,Huber, S.,Bucher, D.,Klint, J.K.,Rodriguez, D.,Tagmose, L.,Chami, M.,Cheng, R.,Hennig, M.,Abdul Rahman, W.
Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators.
Pnas Nexus, 1:pgac083-pgac083, 2022

PubMed Abstract: Kv3 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 Å 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°. 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.

PubMed: 36741467
DOI: 10.1093/pnasnexus/pgac083

Experimental method

ELECTRON MICROSCOPY (3.03 Å)