| 词条 | Pandinus imperator toxin (Pi4) |
| 释义 |
EtymologyThe name Pi4 is the fourth toxin isolated from the scorpion Pandinus imperator, from which Pi1, Pi2, Pi3, and Pi7 have also been isolated.[3] ChemistryPi4 is a peptide, which consists of 38 amino-acids with the following sequence: IEAIRCGGSRDCYRPCQKRTGCPNAKCINKTCKCYGCS[1][4] It contains an α-helix and a β-sheet; it is stabilized by four cysteine-pairings that are crosslinked by four short disulfide bridges. The four disulfide bridges are characteristic for the α-KTX6 subfamily, while most other scorpion toxins contain only three disulfide bridges.[1] The cysteines of Pi4 are paired in the following order: 6C–27C; 12C–32C; 16C–34C; 22C–37C.[1][4] Most disulfide bridges show a left-handed conformation, although in the disulfide bridge between 22C–37C some variation is found. Only the disulfide bridge between 6C–27C shows a right-handed conformation.[1] Target & Mode of actionPi4 blocks different potassium channels, for instance, the Shaker B, Kv1.2, and SK potassium channels. Shaker B channelPi4 binds to Shaker B potassium channels, the Drosophila homologue of the voltage-gated potassium channel Kv1.1.[1] Pi4 reversibly blocks this channel with an IC50 of 3.0 ± 2.2 nM.[1][2] A Pi4 peptide, synthesized with a different C-terminus than the natural Pi4 (COO- instead of COH2N), shows the same binding characteristics as natural Pi4.[1] This suggests that the C-terminus of the peptide Pi4 is not involved in the binding of Pi4 to the Shaker B channel.[1] The residues 26K, 28I, 29N, 33K, and 35Y might be important for Pi4's interaction with Shaker B channels,[1] especially 26K and 35Y, which form a conserved dyad of a lysine and aromatic cluster in other potassium channel toxins.[5] It has been suggested that the positive charge of the lysine mimicks a potassium ion and enters the pore of the potassium channel,[6][7][8] hence occluding the pore opening and inhibiting the ion flux. Kv1.2 channelPi4 blocks the voltage-gated potassium channel Kv1.2.[2] at low concentrations (IC50 8.0 ± 5 pM).[2] No significant effects have been observed on Kv1.1 and Kv1.3 channels at concentrations up to 10 µm.[2] In the binding of the peptide Pi4 to the Kv1.2 channel, the β-sheet structure is thought to play an important role. First, the residue 35Y, located in the β-sheet structure, tightly interacts via electrostatic forces with the aromatic cluster of Kv1.2 channels (344W, 345W and 355Y).[2] Second, the residue 26K becomes stabilized by the four carbonyl oxygen atoms located in the channel of pore formed by four Kv1.2 α-subunits (357D).[2] Finally, the four 332Q residues of the four α-subunits of Kv1.2 channels interact via salt bridges with four subunits of the toxin ring (composed of 10R, 19R, 30K, 33K).[2] SK-channelFurthermore, the Pi4 binds to SK channels, small conductance Ca2+-activated potassium channels.[2] Pi4 competes with apamin, another SK-channel toxin. IC50 is 0.5 ± 0.2 µM.[2] ToxicityScorpion venoms can be toxic for mammals, insects, and crustaceans.[1] Pi4 is lethal in mice upon injection in the ventricular system of the brain at and LD50 value of 0.2 µg/mouse.[2] References1. ^1 2 3 4 5 6 7 8 9 10 {{Cite journal|last=Guijarro|first=J. Iñaki|last2=M'Barek|first2=Sarrah|last3=Gómez-Lagunas|first3=Froylan|last4=Garnier|first4=Damien|last5=Rochat|first5=Hervé|last6=Sabatier|first6=Jean-Marc|last7=Possani|first7=Lourrival D.|last8=Delepierre|first8=Muriel|year=2003|title=Solution structure of Pi4, a short four-disulfide- bridged scorpion toxin specific of potassium channels|journal=Protein Science|volume=12|issue=9|pages=1844–1855|doi=10.1110/ps.03186703|pmid=12930984|pmc=2323982}} 2. ^1 2 3 4 5 6 7 8 9 10 {{Cite journal|last=M'Barek|first=Sarrah|last2=Mosbah|first2=Amor|last3=Sandoz|first3=Guillaume|last4=Fajloun|first4=Ziad|last5=Olamendi-Portugal|first5=Timoteo|last6=Rochat|first6=Hervé|last7=Sampieri|first7=François|last8=Guijarro|first8=J. Iñaki|last9=Mansuelle|first9=Pascal|year=2003|others=Muriel Delepierre, Michel De Waard, and Jean-Marc Sabatier|title=Synthesis and characterization of Pi4, a scorpion toxin from Pandinus imperator that acts on K + channels|journal=Eur. J. Biochem.|volume=270|issue=17|pages=3583–3592|doi=10.1046/j.1432-1033.2003.03743.x}} 3. ^1 {{Cite journal|last=Olamendi-Portugal|first=Timoteo|last2=Gómez-Lagunas|first2=Froylan|last3=Gurrola|first3=Georgina B.|last4=Possani|first4=Lourival D.|year=1998|title=Two similar peptides from the venom of the scorpion pandinus imperator, one highly effective blocker and the other inactive on K+ channels|journal=Toxicon|volume=36|issue=5|pages=759–770|doi=10.1016/s0041-0101(97)00163-3|pmid=9655636}} 4. ^1 {{Cite web|url=http://kaliumdb.org/|title=Kalium: Scorpion Toxins Active on Potassium Channels|website=kaliumdb.org|access-date=2016-10-09}} 5. ^{{Cite journal|last=Dauplais|first=Marc|last2=Lecoq|first2=Alain|last3=Song|first3=Jianxing|last4=Cotton|first4=Joël|last5=Jamin|first5=Nadège|last6=Gilquin|first6=Bernard|last7=Roumestand|first7=Christian|last8=Vita|first8=Claudio|last9=Medeiros|first9=Cleane L. C. de|date=1997-02-14|title=On the Convergent Evolution of Animal Toxins CONSERVATION OF A DIAD OF FUNCTIONAL RESIDUES IN POTASSIUM CHANNEL-BLOCKING TOXINS WITH UNRELATED STRUCTURES|journal=Journal of Biological Chemistry|language=en|volume=272|issue=7|pages=4302–4309|doi=10.1074/jbc.272.7.4302|issn=0021-9258|pmid=9020148}} 6. ^{{Cite journal|last=Goldstein|first=S.A.|last2=Miller|first2=C.|title=Mechanism of charybdotoxin block of a voltage-gated K+ channel|journal=Biophysical Journal|volume=65|issue=4|pages=1613–1619|doi=10.1016/s0006-3495(93)81200-1|pmid=7506068|pmc=1225887|year=1993}} 7. ^{{Cite journal|last=Giangiacomo|first=Kathleen M.|last2=Garcia|first2=Maria L.|last3=McManus|first3=Owen B.|date=1992-07-01|title=Mechanism of iberiotoxin block of the large-conductance calcium-activated potassium channel from bovine aortic smooth muscle|journal=Biochemistry|volume=31|issue=29|pages=6719–6727|doi=10.1021/bi00144a011|issn=0006-2960}} 8. ^{{Cite journal|last=Park|first=Chul-Seung|last2=Miller|first2=Christopher|title=Interaction of charybdotoxin with permeant ions inside the pore of a K+ channel|journal=Neuron|volume=9|issue=2|pages=307–313|doi=10.1016/0896-6273(92)90169-e|year=1992}} 1 : Ion channel toxins |
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