title: Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease.
abstract: The potassium channel Kv1.3 is an attractive pharmacological target for immunomodulation of T cell-mediated autoimmune diseases. Potent and selective blockers of Kv1.3 are potential therapeutics for treating these diseases. Here we describe the design of a new peptide inhibitor that is potent and selective for Kv1.3. Three residues (Gly(11), Ile(28), and Asp(33)) of a scorpion toxin BmKTX were substituted by Arg(11), Thr(28), and His(33), resulting in a new peptide, named ADWX-1. The ADWX-1 peptide blocked Kv1.3 with picomolar affinity (IC(50), 1.89 pM), showing a 100-fold increase in activity compared with the native BmKTX toxin. The ADWX-1 also displayed good selectivity on Kv1.3 over related Kv1.1 and Kv1.2 channels. Furthermore, alanine-scanning mutagenesis was carried out to map the functional residues of ADWX-1 in blocking Kv1.3. Moreover, computational simulation was used to build a structural model of the ADWX-1-Kv1.3 complex. This model suggests that all mutated residues are favorable for both the high potency and selectivity of ADWX-1 toward Kv1.3. While Arg(11) of ADWX-1 interacts with Asp(386) in Kv1.3, Thr(28) and His(33) of ADWX-1 locate right above the selectivity filter-S6 linker of Kv1.3. Together, our data indicate that the specific ADWX-1 peptide would be a viable lead in the therapy of T cell-mediated autoimmune diseases, and the successful design of ADWX-1 suggests that rational design based on the structural model of the peptide-channel complex should accelerate the development of diagnostic and therapeutic agents for human channelopathies.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Yin
authors.forename: Zong-Yun
authors.initials: ZY
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Cao
authors.forename: Ying-Liang
authors.initials: YL
authors.lastname: Wu
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Li
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D010449:Peptide Mapping / Q000379:methods; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012604:Scorpion Venoms / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D051662:Kv1.1 Potassium Channel