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2MUB

Solution structure of the analgesic sea anemone peptide APETx2

Summary for 2MUB
Entry DOI10.2210/pdb2mub/pdb
Related1WXN
NMR InformationBMRB: 25205
DescriptorToxin APETx2 (1 entity in total)
Functional Keywordsdisulfide-rich toxin, defensin fold, toxin, asic3 blocker
Biological sourceAnthopleura elegantissima (Sea anemone)
Cellular locationSecreted : P61542
Total number of polymer chains1
Total formula weight4571.12
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 citationJensen, 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: 25337890
DOI: 10.1021/jm501400p
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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건을2025-07-30부터공개중

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