Chemical synthesis, 3D structure and ASIC binding site of mambalgin-2

Schroeder, Christina I., Rash, Lachlan D., Vila-Farrés, Xavier, Rosengren, K. Johan, Mobli, Mehdi, King, Glenn F., Alewood, Paul F., Craik, David J. and Durek, Thomas (2014) Chemical synthesis, 3D structure and ASIC binding site of mambalgin-2. Angewandte Chemie International Edition, 53 4: 1017-1020. doi:10.1002/anie.201308898

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Author Schroeder, Christina I.
Rash, Lachlan D.
Vila-Farrés, Xavier
Rosengren, K. Johan
Mobli, Mehdi
King, Glenn F.
Alewood, Paul F.
Craik, David J.
Durek, Thomas
Title Chemical synthesis, 3D structure and ASIC binding site of mambalgin-2
Journal name Angewandte Chemie International Edition   Check publisher's open access policy
ISSN 1433-7851
1521-3773
Publication date 2014-01-20
Year available 2013
Sub-type Article (original research)
DOI 10.1002/anie.201308898
Open Access Status File (Author Post-print)
Volume 53
Issue 4
Start page 1017
End page 1020
Total pages 4
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag
Language eng
Abstract Mambalgins are a novel class of snake venom components that exert potent analgesic effects mediated through the inhibition of acid-sensing ion channels (ASICs). The 57-residue polypeptide mambalgin-2 (Ma-2) was synthesized by using a combination of solid-phase peptide synthesis and native chemical ligation. The structure of the synthetic toxin, determined using homonuclear NMR, revealed an unusual three-finger toxin fold reminiscent of functionally unrelated snake toxins. Electrophysiological analysis of Ma-2 on wild-type and mutant ASIC1a receptors allowed us to identify -helix 5, which borders on the functionally critical acidic pocket of the channel, as a major part of the Ma-2 binding site. This region is also crucial for the interaction of ASIC1a with the spider toxin PcTx1, thus suggesting that the binding sites for these toxins substantially overlap. This work lays the foundation for structure-activity relationship (SAR) studies and further development of this promising analgesic peptide.
Formatted abstract
Mambalgins are a novel class of snake venom components that exert potent analgesic effects mediated through the inhibition of acid-sensing ion channels (ASICs). The 57-residue polypeptide mambalgin-2 (Ma-2) was synthesized by using a combination of solid-phase peptide synthesis and native chemical ligation. The structure of the synthetic toxin, determined using homonuclear NMR, revealed an unusual three-finger toxin fold reminiscent of functionally unrelated snake toxins. Electrophysiological analysis of Ma-2 on wild-type and mutant ASIC1a receptors allowed us to identify α-helix 5, which borders on the functionally critical acidic pocket of the channel, as a major part of the Ma-2 binding site. This region is also crucial for the interaction of ASIC1a with the spider toxin PcTx1, thus suggesting that the binding sites for these toxins substantially overlap. This work lays the foundation for structure–activity relationship (SAR) studies and further development of this promising analgesic peptide.
Keyword Ion channels
Native chemical ligation
NMR spectroscopy
Peptides
Solid-phase synthesis
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 569927
Institutional Status UQ
Additional Notes Authors prepress title: "Toxic fingers pick ASIC's pocket: chemical synthesis, 3D structure and ASIC binding site of mambalgin-2". Published under "Venom Peptides". Published online 9 December 2013

 
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Created: Thu, 09 Jan 2014, 01:55:25 EST by Sandrine Ducrot on behalf of Chemistry, Department of