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SOLUTION STRUCTURE OF A TOXIN FROM THE TARANTULA, GRAMMOSTOLA SPATULATA, WHICH INHIBITS MECHANOSENSITIVE ION CHANNELS
Structural highlights
FunctionMTX4_GRARO This cationic hydrophobic peptide inhibits a lot of different channels and has an antimicrobial activity. It blocks mechanosensitive ion channels (also named stretch-activated channels or SACs), without having effect on whole-cell voltage-sensitive currents. Acts by partitioning into the membrane and perturbing the interface between the channel and the lipid bilayer without necessarily being in physical contact with the channel. Inhibits atrial fibrillation as well as the membrane motor of outer hair cells at low doses. It also binds to the voltage sensor of voltage-gated potassium channels from the archaebacterium Aeropyrum pernix (KvAP) without affecting channel gating. It has also a medium toxicity on a large spectra of sodium channels (Nav1.1/SCN1A, Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.4/SCN4A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A), and also inhibits potassium channels Kv11.1/KCNH2 and Kv11.2/KCNH6. It also exhibits antimicrobial activities against the Gram-positive bacteria B.subtilis (MIC=0.5 uM), S.aureus (MIC=2-4 uM), and S.epidermidis (MIC=4-8 uM), and Gram-negative bacteria S.typhimurium (MIC=32.64 uM), P.aeruginosa (MIC=8-16 uM), and E.coli (MIC=8-16 uM).[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedMechanosensitive channels (MSCs) play key roles in sensory processing and have been implicated as primary transducers for a variety of cellular responses ranging from osmosensing to gene expression. This paper presents the first structures of any kind known to interact specifically with MSCs. GsMTx-4 and GsMtx-2 are inhibitor cysteine knot peptides isolated from venom of the tarantula, Grammostola spatulata (Suchyna, T. M., Johnson, J. H., Hamer, K., Leykam, J. F., Gage, D. A., Clemo, H. F., Baumgarten, C. M., and Sachs, F. (2000) J. Gen. Physiol. 115, 583-598). Inhibition of cationic MSCs by the higher affinity GsMtx-4 (K(D) approximately 500 nm) reduced cell size in swollen and hypertrophic heart cells, swelling-activated currents in astrocytes, and stretch-induced arrhythmias in the heart. Despite the relatively low affinity, no cross-reactivity has been found with other channels. Using two-dimensional NMR spectroscopy, we determined the solution structure of GsMTx-4 and a lower affinity (GsMTx-2; K(D) approximately 6 microm) peptide from the same venom. The dominant feature of the two structures is a hydrophobic patch, utilizing most of the aromatic residues and surrounded with charged residues. The spatial arrangement of charged residues that are unique to GsMTx-4 and GsMTx-2 may underlie the selectivity of these peptides. Solution structure of peptide toxins that block mechanosensitive ion channels.,Oswald RE, Suchyna TM, McFeeters R, Gottlieb P, Sachs F J Biol Chem. 2002 Sep 13;277(37):34443-50. Epub 2002 Jun 24. PMID:12082099[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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