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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: 27 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 (7)

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  2. Dilation of ion selectivity filters in cation channels. Huffer K, Tan XF, Fernández-Mariño AI, Dhingra S, Swartz KJ. Trends Biochem Sci 49 417-430 (2024)
  3. Voltage-Gated K+ Channel Modulation by Marine Toxins: Pharmacological Innovations and Therapeutic Opportunities. Turcio R, Di Matteo F, Capolupo I, Ciaglia T, Musella S, Di Chio C, Stagno C, Campiglia P, Bertamino A, Ostacolo C. Mar Drugs 22 350 (2024)
  4. Discovery of Therapeutic Antibodies Targeting Complex Multi-Spanning Membrane Proteins. Stephens AD, Wilkinson T. BioDrugs 38 769-794 (2024)
  5. Electrophysiological evaluation of the effect of peptide toxins on voltage-gated ion channels: a scoping review on theoretical and methodological aspects with focus on the Central and South American experience. Rojas-Palomino J, Gómez-Restrepo A, Salinas-Restrepo C, Segura C, Giraldo MA, Calderón JC. J Venom Anim Toxins Incl Trop Dis 30 e20230048 (2024)
  6. Structural biology and molecular pharmacology of voltage-gated ion channels. Huang J, Pan X, Yan N. Nat Rev Mol Cell Biol 25 904-925 (2024)
  7. Structural modeling of ion channels using AlphaFold2, RoseTTAFold2, and ESMFold. Nguyen PT, Harris BJ, Mateos DL, González AH, Murray AM, Yarov-Yarovoy V. Channels (Austin) 18 2325032 (2024)

Articles citing this publication (19)

  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. 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)
  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. 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)
  6. 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)
  7. 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)
  8. 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)
  9. The binding and mechanism of a positive allosteric modulator of Kv3 channels. Liang Q, Chi G, Cirqueira L, Zhi L, Marasco A, Pilati N, Gunthorpe MJ, Alvaro G, Large CH, Sauer DB, Treptow W, Covarrubias M. Nat Commun 15 2533 (2024)
  10. 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)
  11. Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation. Rödström KEJ, Cloake A, Sörmann J, Baronina A, Smith KHM, Pike ACW, Ang J, Proks P, Schewe M, Holland-Kaye I, Bushell SR, Elliott J, Pardon E, Baukrowitz T, Owens RJ, Newstead S, Steyaert J, Carpenter EP, Tucker SJ. Nat Commun 15 4173 (2024)
  12. 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)
  13. Polymodal K+ channel modulation contributes to dual analgesic and anti-inflammatory actions of traditional botanical medicines. Manville RW, Yoshimura RF, Yeromin AV, Hogenkamp D, van der Horst J, Zavala A, Chinedu S, Arena G, Lasky E, Fisher M, Tracy CR, Othy S, Jepps TA, Cahalan MD, Abbott GW. Commun Biol 7 1059 (2024)
  14. KcsA-Kv1.x chimeras with complete ligand-binding sites provide improved predictivity for screening selective Kv1.x blockers. Szekér P, Bodó T, Klima K, Csóti Á, Hanh NN, Murányi J, Hajdara A, Szántó TG, Panyi G, Megyeri M, Péterfi Z, Farkas S, Gyöngyösi N, Hornyák P. J Biol Chem 300 107155 (2024)
  15. Metal-ion-chelating phenylalanine nanostructures reverse immune dysfunction and sensitize breast tumour to immune checkpoint blockade. Tan M, Cao G, Wang R, Cheng L, Huang W, Yin Y, Ma H, Ho SH, Wang Z, Zhu M, Ran H, Nie G, Wang H. Nat Nanotechnol (2024)
  16. Revealing the Diversity of Sequences, Structures, and Targets of Peptides from South China Sea <i>Macrodactyla doreensis</i> Based on Transcriptomics. Hua Z, Liao Y, Fu J, Li X, Xu Q, Lin L, Huang M, Gao B. Mar Drugs 22 470 (2024)
  17. Salmon louse labial gland enzymes: implications for host settlement and immune modulation. Midtbø HMD, Eichner C, Hamre LA, Dondrup M, Flesland L, Tysseland KH, Kongshaug H, Borchel A, Skoge RH, Nilsen F, Øvergård AC. Front Genet 14 1303898 (2023)
  18. 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)
  19. Unmasking subtype-dependent susceptibility to C-type inactivation in mammalian Kv1 channels. Baronas VA, Wong A, Das D, Lamothe SM, Kurata HT. Biophys J 123 2012-2023 (2024)


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