1wqk
From Proteopedia
Solution structure of APETx1, a specific peptide inhibitor of human Ether-a-go-go-related gene potassium channels from the venom of the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin
Structural highlights
FunctionBDS1_ANTEL Peptide with both antimicrobial and neurotoxin activities. This toxin acts both on ERG potassium channels and sodium channels (PubMed:12815161,PubMed:16497878, PubMed:17473056, PubMed:22972919). It potently and reversibly inhibits human Kv11.1/KCNH2/ERG1 (IC(50)=34 nM) (PubMed:12815161, PubMed:16497878, PubMed:17473056), rat Kv11.1/KCNH2/ERG1 (PubMed:16497878) and Kv11.3/KCNH7/ERG3 (PubMed:17473056) voltage-gated potassium channels in a similar potency. It acts as a gating-modifier toxin that shifts the voltage-dependence of ERG activation in the positive direction and suppresses its current amplitudes elicited by strong depolarizing pulses (PubMed:12815161, PubMed:17473056). On sodium channels, it blocks Nav1.2/SCN2A (EC(50)=31 nM), Nav1.3/SCN3A, Nav1.4/SCN4A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.8/SCN10A (EC(50)=92 nM) (PubMed:22972919). It may act by binding at site 1 or close by, only when the pore is in an open configuration (PubMed:22972919). Shows antibacterial activity against the Gram-negative bacterium S.typhimurium, but not on the bacteria B.subtilis, S.aureus, and P.aeruginosa (PubMed:28796463). In vivo, this toxin does not induce neurotoxic symptoms when injected into mice (PubMed:12815161).[1] [2] [3] [4] Publication Abstract from PubMedAPETx1 is a 42-amino acid toxin purified from the venom of the sea anemone Anthopleura elegantissima. This cysteine-rich peptide possesses three disulfide bridges (C4-C37, C6-C30, and C20-C38). Its pharmacological target is the Ether-a-gogo potassium channel. We herein determine the solution structure of APETx1 by use of conventional two-dimensional 1H-NMR techniques followed by torsion angle dynamics and refinement protocols. The calculated structure of APETx1 belongs to the disulfide-rich all-beta structural family, in which a three-stranded anti-parallel beta-sheet is the only secondary structure. APETx1 is the first Ether-a-gogo effector discovered to fold in this way. We therefore compare the structure of APETx1 to those of the two other known effectors of the Ether-a-gogo potassium channel, CnErg1 and BeKm-1, and analyze the topological disposition of key functional residues proposed by analysis of the electrostatic anisotropy. The interacting surface is made of a patch of aromatic residues (Y5, Y32, and F33) together with two basic residues (K8 and K18) at the periphery of the surface. We pinpoint the absence of the central lysine present in the functional surface of the two other Ether-a-gogo effectors. Solution structure of APETx1 from the sea anemone Anthopleura elegantissima: a new fold for an HERG toxin.,Chagot B, Diochot S, Pimentel C, Lazdunski M, Darbon H Proteins. 2005 May 1;59(2):380-6. PMID:15726634[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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