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Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators.

<div class='caption-title'>Structure of human Kv1.3.</div>
<div class='caption-title'>The Kv1.3 selectivity filter adopts two distinct dilated conformations.</div>
<div class='caption-title'>Multiple nanobodies bind the turret loops and voltage sensing domains of Kv1.3.</div>
Selvakumar P, Fernández-Mariño AI, Khanra N, He C, Paquette AJ, Wang B, Huang R, Smider VV, Rice WJ, Swartz KJ, Meyerson JR
OpenAccess logo Nat Commun 13 3854 (2022)
Related entries: 7ssv, 7ssx, 7ssy, 8dfl

Cited: 13 times
EuropePMC logo PMID: 35788586

Abstract

The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer's voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.

Reviews - 7ssz mentioned but not cited (1)

  1. Structure of the voltage-gated potassium channel KV1.3: Insights into the inactivated conformation and binding to therapeutic leads. Chandy KG, Sanches K, Norton RS. Channels (Austin) 17 2253104 (2023)


Reviews citing this publication (1)

  1. Microglial ion channels: Key players in non-cell autonomous neurodegeneration. Sarkar S. Neurobiol Dis 174 105861 (2022)

Articles citing this publication (11)

  1. Voltage-sensor movements in the Eag Kv channel under an applied electric field. Mandala VS, MacKinnon R. Proc Natl Acad Sci U S A 119 e2214151119 (2022)
  2. Kalium 3.0 is a comprehensive depository of natural, artificial, and labeled polypeptides acting on potassium channels. Krylov NA, Tabakmakher VM, Yureva DA, Vassilevski AA, Kuzmenkov AI. Protein Sci 32 e4776 (2023)
  3. Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175. Oh S, Stix R, Zhou W, Faraldo-Gómez JD, Hite RK. Proc Natl Acad Sci U S A 119 e2208882119 (2022)
  4. Characterization and Chemical Synthesis of Cm39 (α-KTx 4.8): A Scorpion Toxin That Inhibits Voltage-Gated K+ Channel KV1.2 and Small- and Intermediate-Conductance Ca2+-Activated K+ Channels KCa2.2 and KCa3.1. Naseem MU, Gurrola-Briones G, Romero-Imbachi MR, Borrego J, Carcamo-Noriega E, Beltrán-Vidal J, Zamudio FZ, Shakeel K, Possani LD, Panyi G. Toxins (Basel) 15 41 (2023)
  5. Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters. Matamoros M, Ng XW, Brettmann JB, Piston DW, Nichols CG. Nat Commun 14 89 (2023)
  6. Discovery of an Insect Neuroactive Helix Ring Peptide from Ant Venom. Barassé V, Jouvensal L, Boy G, Billet A, Ascoët S, Lefranc B, Leprince J, Dejean A, Lacotte V, Rahioui I, Sivignon C, Gaget K, Ribeiro Lopes M, Calevro F, Da Silva P, Loth K, Paquet F, Treilhou M, Bonnafé E, Touchard A. Toxins (Basel) 15 600 (2023)
  7. Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse. Stix R, Tan XF, Bae C, Fernández-Mariño AI, Swartz KJ, Faraldo-Gómez JD. Sci Adv 9 eadj5539 (2023)
  8. Interactions between selectivity filter and pore helix control filter gating in the MthK channel. Kopec W, Thomson AS, de Groot BL, Rothberg BS. J Gen Physiol 155 e202213166 (2023)
  9. Mutations within the selectivity filter reveal that Kv1 channels have distinct propensities to slow inactivate. Wu X, Gupta K, Swartz KJ. J Gen Physiol 154 e202213222 (2022)
  10. Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2. Shakeel K, Olamendi-Portugal T, Naseem MU, Becerril B, Zamudio FZ, Delgado-Prudencio G, Possani LD, Panyi G. Toxins (Basel) 15 506 (2023)
  11. Selective block of human Kv1.1 channels and an epilepsy-associated gain-of-function mutation by AETX-K peptide. Zhao R, Qasim A, Sophanpanichkul P, Dai H, Nayak M, Sher I, Chill J, Goldstein SAN. FASEB J 38 e23381 (2024)


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