2mub

Solution structure of the analgesic sea anemone peptide APETx2

spinqualitylabelsall models 2mub, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mub is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 1wxn Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [APT2_ANTEL] Potently and selectively blocks the acid-sensing ion channel ASIC3 (ACCN3). The blockade is rapid and reversible. Also inhibits heteromeric ASIC2b-ASIC3 (ACCN1-ACCN3) channel, while it has less affinity for ASIC1b-ASIC3 (ACCN2-ACCN3), ASIC1a-ASIC3 (ACCN2-ASIC3). Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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