2m9l

Solution structure of protoxin-1

spinqualitylabelsall models 2m9l, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2m9l is a 1 chain structure. Full experimental information is available from OCA. Related: 2m9o Activity: Glucokinase, with EC number 2.7.1.2 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed BACKGROUND: The venoms of predators have been an excellent source of diverse highly specific peptides targeting ion channels. Here we describe the first known peptide antagonist of the nociceptor ion channel transient receptor potential ankyrin 1 (TRPA1). RESULTS: We constructed a recombinant cDNA library encoding approximately 100 diverse GPI-anchored peptide toxins (t-toxins) derived from spider venoms and screened this library by coexpression in Xenopus oocytes with TRPA1. This screen resulted in identification of protoxin-I (ProTx-I), a 35-residue peptide from the venom of the Peruvian green-velvet tarantula, Thrixopelma pruriens, as the first known high-affinity peptide TRPA1 antagonist. ProTx-I was previously identified as an antagonist of voltage-gated sodium (NaV) channels. We constructed a t-toxin library of ProTx-I alanine-scanning mutants and screened this library against NaV1.2 and TRPA1. This revealed distinct partially overlapping surfaces of ProTx-I by which it binds to these two ion channels. Importantly, this mutagenesis yielded two novel ProTx-I variants that are only active against either TRPA1or NaV1.2. By testing its activity against chimeric channels, we identified the extracellular loops of the TRPA1 S1-S4 gating domain as the ProTx-I binding site. CONCLUSIONS: These studies establish our approach, which we term "toxineering," as a generally applicable method for isolation of novel ion channel modifiers and design of ion channel modifiers with altered specificity. They also suggest that ProTx-I will be a valuable pharmacological reagent for addressing biophysical mechanisms of TRPA1 gating and the physiology of TRPA1 function in nociceptors, as well as for potential clinical application in the context of pain and inflammation. A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain.,Gui J, Liu B, Cao G, Lipchik AM, Perez M, Dekan Z, Mobli M, Daly NL, Alewood PF, Parker LL, King GF, Zhou Y, Jordt SE, Nitabach MN Curr Biol. 2014 Mar 3;24(5):473-83. doi: 10.1016/j.cub.2014.01.013. Epub 2014 Feb, 13. PMID:24530065 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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