1wt7

Solution structure of BuTX-MTX: a butantoxin-maurotoxin chimera

spinqualitylabelsall models 1wt7 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1wt7 is a 1 chain structure with sequence from Tityus serrulatus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KA121_TITSE Potently blocks Kv1.3/KCNA3, Kv1.2/KCNA2, and Shaker potassium channels (PubMed:24590385) and inhibits high conductance calcium-activated potassium channels (PubMed:10082164). The IC(50) of Kv1.3/KCNN3 and Kv1.2/KCNN2 are 0.55 nM and 6.19 nM respectively (PubMed:24590385). In addition, it stimulates the release of NO, IL-6 and TNF-alpha in J774.1 cells (PubMed:21549737) and presents a pro-inflammatory activity in mice (PubMed:23085190). KAX62_SCOPA Blocks voltage-gated potassium channels Kv1.2/KCNA2 (IC(50)=0.12-0.8 nM), KCa3.1/KCNN4 (IC(50)=1-2.2 nM), Shaker B (IC(50)=2.39-80 nM), Kv1.1/KCNA1 (IC(50)=37-45 or no activity, depending on the study), Kv1.3/KCNA3 (IC(50)=150-180 or no activity, depending on the study). Publication Abstract from PubMed Scorpion toxins interact with their target ion channels through multiple molecular contacts. Because a "gain of function" approach has never been described to evaluate the importance of the molecular contacts in defining toxin affinity, we experimentally examined whether increasing the molecular contacts between a toxin and an ion channel directly impacts toxin affinity. For this purpose, we focused on two scorpion peptides, the well-characterized maurotoxin with its variant Pi1-like disulfide bridging (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as an N-terminal domain provider. BuTX is found to be 60-fold less potent than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues) further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in agreement with docking simulation data showing the importance of this domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain to MTX(Pi1) results in a chimera with five disulfide bridges (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to MTX(Pi1). Docking experiments performed with the 3-D structure of BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the N-terminal domain of BuTX participates in the increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicate that acting on molecular contacts between a toxin and a channel is an efficient strategy to modulate toxin affinity. Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity.,M'Barek S, Chagot B, Andreotti N, Visan V, Mansuelle P, Grissmer S, Marrakchi M, El Ayeb M, Sampieri F, Darbon H, Fajloun Z, De Waard M, Sabatier JM Proteins. 2005 Aug 15;60(3):401-11. PMID:15971207 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Potassium channel toxin 3D structures

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