2MUB
Solution structure of the analgesic sea anemone peptide APETx2
Summary for 2MUB
Entry DOI | 10.2210/pdb2mub/pdb |
Related | 1WXN |
NMR Information | BMRB: 25205 |
Descriptor | Toxin APETx2 (1 entity in total) |
Functional Keywords | disulfide-rich toxin, defensin fold, toxin, asic3 blocker |
Biological source | Anthopleura elegantissima (Sea anemone) |
Cellular location | Secreted : P61542 |
Total number of polymer chains | 1 |
Total formula weight | 4571.12 |
Authors | Mobli, M.,King, G.F.,Rosengren, K.J.,Jensen, J.E. (deposition date: 2014-09-07, release date: 2014-12-24, Last modification date: 2024-11-27) |
Primary citation | Jensen, J.E.,Cristofori-Armstrong, B.,Anangi, R.,Rosengren, K.J.,Lau, C.H.,Mobli, M.,Brust, A.,Alewood, P.F.,King, G.F.,Rash, L.D. 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. J.Med.Chem., 57:9195-9203, 2014 Cited by PubMed Abstract: The 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. PubMed: 25337890DOI: 10.1021/jm501400p PDB entries with the same primary citation |
Experimental method | SOLUTION NMR |
Structure validation
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