8QUD

Cryo-EM Structure of Human Kv3.1 in Complex with Modulator AUT5

Summary for 8QUD

• Entry DOI: 10.2210/pdb8qud/pdb
• EMDB information: 18659 18660
• Descriptor: Potassium voltage-gated channel subfamily C member 1, (5R)-5-ethyl-3-(6-spiro[2H-1-benzofuran-3,1'-cyclopropane]-4-yloxypyridin-3-yl)imidazolidine-2,4-dione, ZINC ION, ... (7 entities in total)
• Functional Keywords: modulator, homotetramer, voltage-gated potassium channel, membrane protein, kv3.1, kcnc1
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 242241.13

Authors

Chi, G.,Mckinley, G.,Marsden, B.,Pike, A.C.W.,Ye, M.,Brooke, L.M.,Bakshi, S.,Lakshminarayana, B.,Pilati, N.,Marasco, A.,Gunthorpe, M.,Alvaro, G.S.,Large, C.H.,Williams, E.,Sauer, D.B. (deposition date: 2023-10-16, release date: 2024-04-03)

Primary citation

Liang, Q.,Chi, G.,Cirqueira, L.,Zhi, L.,Marasco, A.,Pilati, N.,Gunthorpe, M.J.,Alvaro, G.,Large, C.H.,Sauer, D.B.,Treptow, W.,Covarrubias, M.
The binding and mechanism of a positive allosteric modulator of Kv3 channels.
Nat Commun, 15:2533-2533, 2024

PubMed Abstract: Small-molecule modulators of diverse voltage-gated K (Kv) channels may help treat a wide range of neurological disorders. However, developing effective modulators requires understanding of their mechanism of action. We apply an orthogonal approach to elucidate the mechanism of action of an imidazolidinedione derivative (AUT5), a highly selective positive allosteric modulator of Kv3.1 and Kv3.2 channels. AUT5 modulation involves positive cooperativity and preferential stabilization of the open state. The cryo-EM structure of the Kv3.1/AUT5 complex at a resolution of 2.5 Å reveals four equivalent AUT5 binding sites at the extracellular inter-subunit interface between the voltage-sensing and pore domains of the channel's tetrameric assembly. Furthermore, we show that the unique extracellular turret regions of Kv3.1 and Kv3.2 essentially govern the selective positive modulation by AUT5. High-resolution apo and bound structures of Kv3.1 demonstrate how AUT5 binding promotes turret rearrangements and interactions with the voltage-sensing domain to favor the open conformation.

PubMed: 38514618
DOI: 10.1038/s41467-024-46813-8

Experimental method

ELECTRON MICROSCOPY (2.5 Å)