Receptor-targeting mechanisms of pain-causing toxins: How ow?

Bohlen, Christopher J.; Julius, David

doi:10.1016/j.toxicon.2012.04.336

Cited by 61 publications

(61 citation statements)

References 119 publications

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“…Duplication and hypermutability of toxin genes accelerates the neo-functionalization of protein scaffolds commonly found in animal venoms, such as those belonging to the prolific Kunitz, PLA2, and inhibitor cysteine knot families (Bohlen and Julius, 2012). The comparison of MitTx with other known Kunitz and PLA2 structures illustrates the repeated use of regions peripheral to their compact and rigid cores in specifying interactions with subunits or physiological targets.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, snake (Bohlen et al, 2011; Diochot et al, 2012), spider (Escoubas et al, 2000) and sea anemone toxins (Diochot et al, 2004; Karczewski et al, 2010) have been identified that elicit or suppress pain by selectively activating or blocking ASICs (Bohlen and Julius, 2012; Chen et al, 2005; Karczewski et al, 2010). In addition to validating a role for ASICs in nociception and pain sensation, peptide toxins provide powerful tools to arrest ASICs in specific conformational states for pharmacological, biophysical, and structural studies (Baconguis and Gouaux, 2012; Baconguis et al, 2013; Bohlen et al, 2011; Chen et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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X-Ray Structure of Acid-Sensing Ion Channel 1–Snake Toxin Complex Reveals Open State of a Na+-Selective Channel

Baconguis

Bohlen

Goehring

et al. 2014

Cell

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280

503

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Summary Acid sensing ion channels (ASICs) detect extracellular protons produced during inflammation or ischemic injury and belong to the super family of degenerin/epithelial sodium channels. Here, we determine the cocrystal structure of chicken ASIC1a with MitTx, a pain-inducing toxin from the Texas coral snake, to define the structure of the open state of ASIC1a. In the MitTx-bound open state and in the previously determined low pH desensitized state, TM2 is a discontinuous α-helix in which the Gly-Ala-Ser selectivity filter adopts an extended, belt-like conformation, swapping the cytoplasmic one-third of TM2 with an adjacent subunit. Gly 443 residues of the selectivity filter provide a ring of 3 carbonyl oxygen atoms with a radius of ~3.6 Å, presenting an energetic barrier for hydrated ions. The ASIC1a-MitTx complex illuminates the mechanism of MitTx action, defines the structure of the selectivity filter of voltage-independent, sodium-selective ion channels and captures the open state of an ASIC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

X-Ray Structure of Acid-Sensing Ion Channel 1–Snake Toxin Complex Reveals Open State of a Na+-Selective Channel

Baconguis

Bohlen

Goehring

et al. 2014

Cell

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280

503

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“…Some of these probably act indirectly by stimulating pathways that can sensitise TRPV1 function (Bohlen and Julius 2012), but the toxins from tarantula spiders act directly. These cysteine-rich (inhibitor cysteine knot, ICK) toxins contain internal disulfide bonds that stabilise the structure of the toxin.…”

Section: Vanillotoxinsmentioning

confidence: 99%

Trpv1

Bevan¹,

Quallo²,

Andersson³

2014

Handbook of Experimental Pharmacology

154

125

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TRPV1 is a well-characterised channel expressed by a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non-neuronal sites in the mammalian body. Functionally, TRPV1 acts as a sensor for noxious heat (greater than ~42 °C). It can also be activated by some endogenous lipid-derived molecules, acidic solutions (pH < 6.5) and some pungent chemicals and food ingredients such as capsaicin, as well as by toxins such as resiniferatoxin and vanillotoxins. Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which (e.g. AKAP79/150) are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50-100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed. Studies with TRPV1 agonists and antagonists and Trpv1 (-/-) mice have suggested a role for TRPV1 in pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder. TRPV1 antagonists have advanced to clinical trials where findings of drug-induced hyperthermia and loss of heat sensitivity have raised questions about the viability of this therapeutic approach.

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“…This signature may be reduced to the more general principal structural motif CX 6 CX n CC (C 1 X 6 C 2 X 5 C 4 C 5 in our case), and extra structural motif CXCX n CXC (C 6 XC 7 X m C 8 XC 9 in our case) that are characteristic of spider neurotoxins [23]. The principal structural motif and the extra structural motif in turn conform to the more general ICK motif CX 2-7 CX 3-11 CX 0-7 CX 1-17 CX [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] …”

Section: Ottx Sequence Analysismentioning

confidence: 96%

“…For instance, Agelenopsis aperta produces an array of a-agatoxins (low-molecular-mass blockers of post-synaptic glutamate receptors), l-agatoxins (peptide activators of sodium channels) and x-agatoxins (peptide blockers of diverse calcium channels) [4]. With the recent description of compounds that affect 'unconventional' targets, such as pain receptors in humans [5,6], the pharmacological potential of spider venom seems vast but largely unexplored. Only a dozen or so species have been investigated in detail, representing a minor faction of the known biodiversity.…”

mentioning

confidence: 99%

Spider toxins comprising disulfide‐rich and linear amphipathic domains: a new class of molecules identified in the lynx spider Oxyopes takobius

et al. 2013

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In addition to the conventional neurotoxins and cytotoxins, venom of the lynx spider Oxyopes takobius was found to contain two-domain modular toxins named spiderines: OtTx1a, 1b, 2a and 2b. These toxins show both insecticidal activity (a median lethal dose against flesh fly larvae of 75 lgÁg À1) and potent antimicrobial effects (minimal inhibitory concentrations in the range 0.1-10 lM). Full sequences of the purified spiderines were established by a combination of Edman degradation, mass spectrometry and cDNA cloning. They are relatively large molecules (~110 residues, 12.0-12.5 kDa) and consist of two distinct modules separated by a short linker. The N-terminal part (~40 residues) contains no cysteine residues, is highly cationic, forms amphipathic a-helical structures in a membrane-mimicking environment, and shows potent cytolytic effects on cells of various origins. The C-terminal part (~60 residues) is disulfide-rich (five S-S bonds), and contains the inhibitor cystine knot (ICK/knottin) signature. The N-terminal part of spiderines is very similar to linear cytotoxic peptides found in various organisms, whereas the C-terminal part corresponds to the usual spider neurotoxins. We synthesized the modules of OtTx1a and compared their activity to that of full-length mature toxin produced recombinantly, highlighting the importance of the N-terminal part, which retained full-length toxin activity in both insecticidal and antimicrobial assays. The unique structure of spiderines completes the range of two-domain spider toxins. DatabaseThe protein sequences of the spiderines (OtTx) reported in this paper have been submitted to the UniProt Knowledgebase (UniProtKB) under accession numbers P86716-P86719, and the nucleotide sequences encoding OtTx have been submitted to the GenBank under accession numbers JX134894-JX134897.

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Receptor-targeting mechanisms of pain-causing toxins: How ow?

Cited by 61 publications

References 119 publications

X-Ray Structure of Acid-Sensing Ion Channel 1–Snake Toxin Complex Reveals Open State of a Na+-Selective Channel

X-Ray Structure of Acid-Sensing Ion Channel 1–Snake Toxin Complex Reveals Open State of a Na+-Selective Channel

Trpv1

Spider toxins comprising disulfide‐rich and linear amphipathic domains: a new class of molecules identified in the lynx spider Oxyopes takobius

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