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J Biol Chem
2016 Feb 05;2916:2616-29. doi: 10.1074/jbc.M115.702373.
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Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition.
Mourier G
,
Salinas M
,
Kessler P
,
Stura EA
,
Leblanc M
,
Tepshi L
,
Besson T
,
Diochot S
,
Baron A
,
Douguet D
,
Lingueglia E
,
Servent D
.
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Mambalgins are peptides isolated from mamba venom that specifically inhibit a set of acid-sensing ion channels (ASICs) to relieve pain. We show here the first full stepwise solid phase peptide synthesis of mambalgin-1 and confirm the biological activity of the synthetic toxin both in vitro and in vivo. We also report the determination of its three-dimensional crystal structure showing differences with previously described NMR structures. Finally, the functional domain by which the toxin inhibits ASIC1a channels was identified in its loop II and more precisely in the face containing Phe-27, Leu-32, and Leu-34 residues. Moreover, proximity between Leu-32 in mambalgin-1 and Phe-350 in rASIC1a was proposed from double mutant cycle analysis. These data provide information on the structure and on the pharmacophore for ASIC channel inhibition by mambalgins that could have therapeutic value against pain and probably other neurological disorders.
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010, Pubmed
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010,
Pubmed
Baconguis,
Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes.
2012,
Pubmed
Baron,
Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels.
2013,
Pubmed
Baron,
Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives.
2015,
Pubmed
Chowdhury,
A self-consistent approach for determining pairwise interactions that underlie channel activation.
2014,
Pubmed
,
Xenbase
Ciccone,
Transthyretin complexes with curcumin and bromo-estradiol: evaluation of solubilizing multicomponent mixtures.
2015,
Pubmed
Dawson,
Structure of the acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1.
2012,
Pubmed
Deval,
Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems.
2015,
Pubmed
Diederichs,
Better models by discarding data?
2013,
Pubmed
Diochot,
Black mamba venom peptides target acid-sensing ion channels to abolish pain.
2012,
Pubmed
,
Xenbase
Diochot,
Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain.
2016,
Pubmed
,
Xenbase
Emsley,
Features and development of Coot.
2010,
Pubmed
Fruchart-Gaillard,
Engineering of three-finger fold toxins creates ligands with original pharmacological profiles for muscarinic and adrenergic receptors.
2012,
Pubmed
Fruchart-Gaillard,
Different interactions between MT7 toxin and the human muscarinic M1 receptor in its free and N-methylscopolamine-occupied states.
2008,
Pubmed
Hidalgo,
Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor.
1995,
Pubmed
,
Xenbase
Kabsch,
XDS.
2010,
Pubmed
McCoy,
Simple algorithm for a maximum-likelihood SAD function.
2004,
Pubmed
Mourier,
Chemical synthesis of MT1 and MT7 muscarinic toxins: critical role of Arg-34 in their interaction with M1 muscarinic receptor.
2003,
Pubmed
Murshudov,
REFMAC5 for the refinement of macromolecular crystal structures.
2011,
Pubmed
Mutter,
Pseudo-prolines (psi Pro) for accessing "inaccessible" peptides.
1995,
Pubmed
Newman,
Novel buffer systems for macromolecular crystallization.
2004,
Pubmed
Noël,
Current perspectives on acid-sensing ion channels: new advances and therapeutic implications.
2010,
Pubmed
Pan,
One-pot hydrazide-based native chemical ligation for efficient chemical synthesis and structure determination of toxin Mambalgin-1.
2014,
Pubmed
Saez,
A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a.
2011,
Pubmed
Saez,
Molecular dynamics and functional studies define a hot spot of crystal contacts essential for PcTx1 inhibition of acid-sensing ion channel 1a.
2015,
Pubmed
,
Xenbase
Salinas,
Binding site and inhibitory mechanism of the mambalgin-2 pain-relieving peptide on acid-sensing ion channel 1a.
2014,
Pubmed
Schroeder,
Chemical synthesis, 3D structure, and ASIC binding site of the toxin mambalgin-2.
2014,
Pubmed
Terwilliger,
Automated structure solution, density modification and model building.
2002,
Pubmed
Terwilliger,
Decision-making in structure solution using Bayesian estimates of map quality: the PHENIX AutoSol wizard.
2009,
Pubmed
Vagin,
Molecular replacement with MOLREP.
2010,
Pubmed
Waldmann,
A proton-gated cation channel involved in acid-sensing.
1997,
Pubmed
,
Xenbase
Wemmie,
Acid-sensing ion channels in pain and disease.
2013,
Pubmed
Woolf,
Pain: morphine, metabolites, mambas, and mutations.
2013,
Pubmed