2mub
From Proteopedia
Solution structure of the analgesic sea anemone peptide APETx2
Structural highlights
FunctionBDS2_ANTEL This toxin potently blocks acid-sensing ion channel ASIC3 homotrimers and heterotrimers containing ASIC3 (composed with isoforms of ASIC1 and ASIC2) (PubMed:15044953). It also weakly inhibits potassium channels, and sodium channels (PubMed:15044953, PubMed:21943094, PubMed:22972919, PubMed:25337890). On homomeric ASIC3, this protein shows IC(50)=57-87 nM on rat, 37.3 nM on mouse and 175 nM on human channels (PubMed:15044953, PubMed:18923424, PubMed:19306891, PubMed:20813121, PubMed:21943094, PubMed:22851922, PubMed:22851929). The blockade is rapid and reversible (PubMed:15044953). On heterotrimeric forms, the toxin is less potent (IC(50)=117 nM on rat ASIC2b-ASIC3 channel, 900 nM on rat ASIC1b-ASIC3, and 2 uM on rat ASIC1a-ASIC3) (PubMed:15044953). It weakly inhibits Kv3.4/KCNC4 potassium channels (3 uM of the toxin inhibits 38% of Kv3.4 current) (PubMed:15044953). It reversibly and voltage-dependently inhibits hKv11.1/KCNH2/ERG1 potassium channels (IC(50)=1.21 uM), inhibiting both peak and tail currents without action on channel inactivation (PubMed:25337890). It weakly inhibits rNav1.2/SCN2A (EC(50)=114 nM), rNav1.6/SCN8A current (17% at 1 uM of the toxin) and Nav1.8/SCN10A (IC(50)=6.6 uM on human channels expressed in oocytes, EC(50)=55 nM on rat channels expressed in oocytes, and 2.6 uM on rat channels in DRG neurons) (PubMed:21943094, PubMed:22972919). It may act on sodium channels by binding at site 1 or close by, when the pore is in an open configuration (PubMed:22972919). In vivo, central injection does not induce neurotoxin symptoms in mice even after 24 hours (PubMed:15044953). However, it abolishes acid-induced pain in rats (PubMed:18923424).[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedThe sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-activity relationship study of APETx2. Determination of a high-resolution structure of APETx2 combined with scanning mutagenesis revealed a cluster of aromatic and basic residues that mediate its interaction with ASIC3. We show that APETx2 also inhibits the off-target hERG channel by reducing the maximal current amplitude and shifting the voltage dependence of activation to more positive potentials. Electrophysiological screening of selected APETx2 mutants revealed partial overlap between the surfaces on APETx2 that mediate its interaction with ASIC3 and hERG. Characterization of the molecular basis of these interactions is an important first step toward the rational design of more selective APETx2 analogues. Understanding the Molecular Basis of Toxin Promiscuity: The Analgesic Sea Anemone Peptide APETx2 Interacts with Acid-Sensing Ion Channel 3 and hERG Channels via Overlapping Pharmacophores.,Jensen JE, Cristofori-Armstrong B, Anangi R, Rosengren KJ, Lau CH, Mobli M, Brust A, Alewood PF, King GF, Rash LD J Med Chem. 2014 Nov 13;57(21):9195-203. doi: 10.1021/jm501400p. Epub 2014 Nov 4. PMID:25337890[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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