7WF4

Composite map of human Kv1.3 channel in dalazatide-bound state with beta subunits

Summary for 7WF4

• Entry DOI: 10.2210/pdb7wf4/pdb
• EMDB information: 32460
• Descriptor: Potassium voltage-gated channel subfamily A member 3, Voltage-gated potassium channel subunit beta-2, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: ion channel, kv channel, potassium channel, peptide toxin, shk, dalazatide, selectivity filter, molecular dynamics simulation, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 326859.70

Authors

Tyagi, A.,Ahmed, T.,Jian, S.,Bajaj, S.,Ong, S.T.,Goay, S.S.M.,Zhao, Y.,Vorobyov, I.,Tian, C.,Chandy, K.G.,Bhushan, S. (deposition date: 2021-12-25, release date: 2022-02-09, Last modification date: 2024-11-13)

Primary citation

Tyagi, A.,Ahmed, T.,Jian, S.,Bajaj, S.,Ong, S.T.,Goay, S.S.M.,Zhao, Y.,Vorobyov, I.,Tian, C.,Chandy, K.G.,Bhushan, S.
Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed Abstract: We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide-Kv1.3). Both the apo-Kv1.3 and dalazatide-Kv1.3 structures are in an activated state based on their depolarized voltage sensor and open inner gate. In apo-Kv1.3, the aromatic residue in the signature sequence (Y447) adopts a position that diverges 11 Å from other K channels. The outer pore is significantly rearranged, causing widening of the selectivity filter and perturbation of ion binding within the filter. This conformation is stabilized by a network of intrasubunit hydrogen bonds. In dalazatide-Kv1.3, binding of dalazatide to the channel's outer vestibule narrows the selectivity filter, Y447 occupies a position seen in other K channels, and this conformation is stabilized by a network of intersubunit hydrogen bonds. These remarkable rearrangements in the selectivity filter underlie Kv1.3's transition into the drug-blocked state.

PubMed: 35091471
DOI: 10.1073/pnas.2113536119

Experimental method

ELECTRON MICROSCOPY (3.4 Å)