GsMTx-4

Last updated
M-theraphotoxin-Gr1a
GsMTx-4.png
Identifiers
Organism Grammostola rosea
SymbolGsMTx-4
PDB 1LU8
UniProt Q7YT39
Search for
Structures Swiss-model
Domains InterPro
GsMTx-4
Names
IUPAC name
glycyl-cysteinyl-leucyl-alpha-glutamyl-phenylalanyl-tryptophyl-tryptophyl-lysyl-cysteinyl-asparagyl-prolyl-asparagyl-alpha-aspartyl-alpha-aspartyl-lysyl-cysteinyl-cysteinyl-arginyl-prolyl-lysyl-leucyl-lysyl-cysteinyl-seryl-lysyl-leucyl-phenylalanyl-lysyl-leucyl-cysteinyl-asparagyl-phenylalanyl-seryl-phenylalaninamide (2->17),(9->23),(16->30)-tris(disulfide)
Other names
  • M-TRTx-Gr1a
  • M-theraphotoxin-Gr1a
Identifiers
3D model (JSmol)
PubChem CID
  • InChI=1S/C185H273N49O45S6/c1-98(2)72-121-160(255)203-114(54-27-33-65-188)156(251)229-141-96-284-283-95-140-178(273)225-134(84-147(195)239)184(279)234-71-39-60-144(234)182(277)224-131(83-146(194)238)170(265)222-133(86-151(245)246)172(267)223-132(85-150(243)244)171(266)206-116(56-29-35-67-190)158(253)230-142(97-285-282-94-139(177(272)221-130(82-145(193)237)169(264)218-127(79-105-46-19-12-20-47-105)166(261)226-136(91-236)174(269)211-120(152(196)247)76-102-40-13-9-14-41-102)231-163(258)124(75-101(7)8)214-153(248)112(52-25-31-63-186)204-164(259)125(77-103-42-15-10-16-43-103)217-162(257)123(74-100(5)6)213-154(249)113(53-26-32-64-187)207-173(268)135(90-235)227-179(141)274)180(275)232-138(176(271)210-119(58-37-69-199-185(197)198)183(278)233-70-38-59-143(233)181(276)209-117(155(250)212-121)57-30-36-68-191)93-281-280-92-137(202-148(240)87-192)175(270)215-122(73-99(3)4)161(256)208-118(61-62-149(241)242)159(254)216-126(78-104-44-17-11-18-45-104)165(260)219-129(81-107-89-201-111-51-24-22-49-109(107)111)168(263)220-128(80-106-88-200-110-50-23-21-48-108(106)110)167(262)205-115(157(252)228-140)55-28-34-66-189/h9-24,40-51,88-89,98-101,112-144,200-201,235-236H,25-39,52-87,90-97,186-192H2,1-8H3,(H2,193,237)(H2,194,238)(H2,195,239)(H2,196,247)(H,202,240)(H,203,255)(H,204,259)(H,205,262)(H,206,266)(H,207,268)(H,208,256)(H,209,276)(H,210,271)(H,211,269)(H,212,250)(H,213,249)(H,214,248)(H,215,270)(H,216,254)(H,217,257)(H,218,264)(H,219,260)(H,220,263)(H,221,272)(H,222,265)(H,223,267)(H,224,277)(H,225,273)(H,226,261)(H,227,274)(H,228,252)(H,229,251)(H,230,253)(H,231,258)(H,232,275)(H,241,242)(H,243,244)(H,245,246)(H4,197,198,199)
    Key: WVDNTWXIIKNMHY-UHFFFAOYSA-N
  • [H]NCC(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H]3CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC4=CC=CC=C4)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC4=CNC5=C4C=CC=C5)NC(=O)[C@H](CC4=CNC5=C4C=CC=C5)NC(=O)[C@H](CC4=CC=CC=C4)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(N)=O
Properties
C185H273N49O45S6
Molar mass 4095.88 g·mol−1
1 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Grammostola mechanotoxin #4 (GsMTx-4, GsMTx4, GsMTx-IV), also known as M-theraphotoxin-Gr1a (M-TRTX-Gr1a), is a neurotoxin isolated from the venom of the spider Chilean rose tarantula Grammostola spatulate (or Grammostola rosea ). [1] This amphiphilic peptide, which consists of 35 amino acids, belongs to the inhibitory cysteine knot (ICK) peptide family. [2] It reduces mechanical sensation by inhibiting mechanosensitive channels (MSCs). [3]

Contents

GsMTx-4 also serves as a cationic antimicrobial peptide against Gram-positive bacteria. [4]

Source

GsMTx-4 was isolated from the venom of Grammostola spatulata. After a blocking effect on mechanosensitive channels of the spider venom was detected in 1996, [5] GsMTx-4 was isolated and identified from the venom later in 2000. [1] Its concentration in the venom is ∼2 mM.

Chemistry

Structure

GsMTx-4 has a polypeptide chain of 35 amino acids with the sequence GCLEF-WWKCN-PNDDK-CCRPK-LKCSK-LFKLC-NFSF, the C-terminus is amidated. The toxin is an amphipathic peptide consisting of a large hydrophobic patch which is surrounded by a ring of six polar lysine residues. These hydrophobic residues enable the toxin to carry an overall charge of +5. The toxin contains three intramolecular disulfide bonds that contribute to the formation of its inhibitor cystine knot (ICK). [2]

Homology

GsMTx-4 shares less than 50% of its sequence homology with all other known peptide toxins. The highest percentage of sequence homology is shared with other tarantula toxins that block voltage-gated calcium channels and voltage-gated potassium channels. The ICK, as well as the residues F4, D13, and L20, are conserved in these tarantula toxins. [1]

Properties

Like other peptides belonging to the super-family of the ICK, GsMTx-4 is amphipathic. [6] Therefore, GsMTx-4 is able to interact with the hydrophobic side of the lipid bilayer. It can insert itself into the membrane by binding to anionic and cationic groups based on hydrophobic and electrostatic interactions. However, GsMTx-4 has a weak selectivity for the anionic phospholipids over the zwitterionic phospholipids of the lipid bilayer compared to other ICK peptides. [7]

For all ICK blocker peptides, the dominating aromatic residues in the hydrophobic face are widely considered to promote the binding and adsorption of the peptide to the lipid bilayer by positively contributing to its bilayer partitioning energy. Compared with other ICK peptides, GsMTx-4 has a relatively high content of lysine residues, which causes the peptide to be more positively charged. This is important for its orientation and depth of the peptide penetration into the lipid bilayer. [6]

Target

GsMTx-4 mainly targets mechanosensitive channels from the Piezo [8] and TRP [9] families, such as Piezo1 [8] and TRPC6 [9] which are generally bilayer tension-sensitive. This corresponds to the strong bilayer partitioning energy of GsMTx-4. It also targets a spectrum of voltage-dependent sodium channels (human Nav1.1- Nav1.7), [10] human ERG channels (Kv11.1 and Kv11.2), [10] and acetylcholine receptors. [11]

Mode of action

The molecular mechanism of inhibiting mechanosensitive channels by GsMTx-4 is bilayer-dependent. [6] [12] Rather than directly binding to the gating structures like other ICK peptides do [4] , GsMTx4 makes the mechanosensitive channels less sensitive to mechanical tension of the bilayer membrane. By its tension-dependent insertion into the membrane, GsMTx4 is thought to distort the distribution of tension near mechanosensitive channels, which will make the transfer of force from the bilayer to the channel less efficient. [6] Unlike other ICK peptides, the action of GsMTx-4 is not stereospecific, as both L- and D-GsMTx-4 can block MSCs. [12]

Binding affinity

Published KD value and IC50 values are listed here.

KD value and IC50 values of GsMTx-4
KDIC50
Piezo1 [8] ~155 nM-
Nav1.1-1.7 [10] -7.4-14.1 μM
Kv11.1-11.2 [10] -10.9-11 μM

Therapeutic use

GsMTx-4 might play a role in the treatment of volume-activated arrhythmias or muscular dystrophy; it potentially has good therapeutic properties because it is well tolerated following injection in mice, it is non-immunogenic, biologically stable, does not directly interact with MSCs, and has a long pharmacokinetic lifetime. [13]

Related Research Articles

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

<span class="mw-page-title-main">Chilean rose tarantula</span> Species of arachnid

The Chilean rose tarantula, also known as the rose hair tarantula, the Chilean fire tarantula, or the Chilean red-haired tarantula, is probably the most common species of tarantula available in American and European pet stores today, due to the large number of wild-caught specimens exported cheaply from their native Chile into the pet trade. The species is also known from Bolivia and Argentina.

Poneratoxin is a paralyzing neurotoxic peptide made by the bullet ant Paraponera clavata. It prevents inactivation of voltage gated sodium channels and therefore blocks the synaptic transmission in the central nervous system. Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. It is rated as a 4 plus on the Schmidt sting pain index, the highest possible rating with that system, and its effects can cause waves of pain up to twelve hours after a single sting. Schmidt describes it as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel." It is additionally being studied for its uses in biological insecticides.

<span class="mw-page-title-main">Heteropodatoxin</span>

Heteropodatoxins are peptide toxins from the venom of the giant crab spider Heteropoda venatoria, which block Kv4.2 voltage-gated potassium channels.

Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

<span class="mw-page-title-main">Psalmotoxin</span>

Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.

<span class="mw-page-title-main">Phrixotoxin</span>

Phrixotoxins are peptide toxins derived from the venom of the Chilean copper tarantula Phrixotrichus auratus, also named Paraphysa scrofa. Phrixotoxin-1 and -2 block A-type voltage-gated potassium channels; phrixotoxin-3 blocks voltage-gated sodium channels. Similar toxins are found in other species, for instance the Chilean rose tarantula.

<span class="mw-page-title-main">Guangxitoxin</span>

Guangxitoxin, also known as GxTX, is a peptide toxin found in the venom of the tarantula Plesiophrictus guangxiensis. It primarily inhibits outward voltage-gated Kv2.1 potassium channel currents, which are prominently expressed in pancreatic β-cells, thus increasing insulin secretion.

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.

Theraphosa leblondi toxin (TLTx) is a toxin occurring in three different forms (subtypes) that are purified and sequenced from the venom of the giant tarantula Theraphosa blondi. This toxin selectively inhibits Kv4.2 voltage-gated potassium channels by acting as a gating modifier.

Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.

Covalitoxin-II is a peptide toxin that is produced by the spider Coremiocnemis validus. It can induce excitatory, non-lethal behavioral symptoms like quivering and jerking in crickets.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

GTx1-15 is a toxin from the Chilean tarantula venom that acts as both a voltage-gated calcium channel blocker and a voltage-gated sodium channel blocker.

Frederick Sachs is an American biologist. He is a SUNY Distinguished Professor in the University at Buffalo's Department of Physiology and Biophysics.

μ-THTX-Cl6a, also known as Cl6a, is a 33-residue peptide toxin extracted from the venom of the spider Cyriopagopus longipes. The toxin acts as an inhibitor of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (NaV1.7), thereby causing sustained reduction of NaV1.7 currents.

<span class="mw-page-title-main">GiTx1</span>

GiTx1 (β/κ-theraphotoxin-Gi1a) is a peptide toxin present in the venom of Grammostola iheringi. It reduces both inward and outward currents by blocking voltage-gated sodium and potassium channels, respectively.

Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels., voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation

<span class="mw-page-title-main">Double-knot toxin</span>

Double-knot toxin (DkTx), also known as Tau-theraphotoxin-Hs1a or Tau-TRTX-Hs1a, is a toxin found in the venom of the Chinese Bird spider, a tarantula species primarily living in the Guangxi province of China. This toxin, characterized by its bivalent structure of two Inhibitor Cysteine Knots (ICK), is thought to induce excruciating and long-lasting pain by activating the transient receptor potential vanilloid 1 (TRPV1) channel.

Cl6b (μ-THTX-Cl6b) is a peptide toxin from the venom of the spider Cyriopagopus longipes. It acts as a sodium channel blocker: Cl6b significantly and persistently reduces currents through the tetrodotoxin-sensitive sodium channels NaV1.2-1.4, NaV1.6, and NaV1.7.

References

  1. 1 2 3 Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, et al. (May 2000). "Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels". The Journal of General Physiology. 115 (5): 583–598. doi:10.1085/jgp.115.5.583. PMC   2217226 . PMID   10779316.
  2. 1 2 Oswald RE, Suchyna TM, McFeeters R, Gottlieb P, Sachs F (September 2002). "Solution structure of peptide toxins that block mechanosensitive ion channels". The Journal of Biological Chemistry. 277 (37): 34443–34450. doi: 10.1074/jbc.M202715200 . PMID   12082099.
  3. ↑ Park SP, Kim BM, Koo JY, Cho H, Lee CH, Kim M, et al. (July 2008). "A tarantula spider toxin, GsMTx4, reduces mechanical and neuropathic pain". Pain. 137 (1): 208–217. doi:10.1016/j.pain.2008.02.013. PMID   18359568. S2CID   23399357.
  4. 1 2 Suchyna TM (November 2017). "Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology". Progress in Biophysics and Molecular Biology. Cardiac Mechanics and Electrics: it takes two to tango. 130 (Pt B): 244–253. doi:10.1016/j.pbiomolbio.2017.07.011. PMC   5716857 . PMID   28778608.
  5. ↑ Chen Y, Simasko SM, Niggel J, Sigurdson WJ, Sachs F (June 1996). "Ca2+ uptake in GH3 cells during hypotonic swelling: the sensory role of stretch-activated ion channels". The American Journal of Physiology. 270 (6 Pt 1): C1790–C1798. doi:10.1152/ajpcell.1996.270.6.C1790. PMID   8764163.
  6. 1 2 3 4 Gnanasambandam R, Ghatak C, Yasmann A, Nishizawa K, Sachs F, Ladokhin AS, et al. (January 2017). "GsMTx4: Mechanism of Inhibiting Mechanosensitive Ion Channels". Biophysical Journal. 112 (1): 31–45. Bibcode:2017BpJ...112...31G. doi:10.1016/j.bpj.2016.11.013. PMC   5231890 . PMID   28076814.
  7. ↑ Posokhov YO, Gottlieb PA, Morales MJ, Sachs F, Ladokhin AS (August 2007). "Is lipid bilayer binding a common property of inhibitor cysteine knot ion-channel blockers?". Biophysical Journal. 93 (4): L20–L22. Bibcode:2007BpJ....93L..20P. doi:10.1529/biophysj.107.112375. PMC   1929044 . PMID   17573432.
  8. 1 2 3 Bae C, Sachs F, Gottlieb PA (July 2011). "The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4". Biochemistry. 50 (29): 6295–6300. doi:10.1021/bi200770q. PMC   3169095 . PMID   21696149.
  9. 1 2 Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL (October 2006). "A common mechanism underlies stretch activation and receptor activation of TRPC6 channels". Proceedings of the National Academy of Sciences of the United States of America. 103 (44): 16586–16591. Bibcode:2006PNAS..10316586S. doi: 10.1073/pnas.0606894103 . PMC   1637625 . PMID   17056714.
  10. 1 2 3 4 Redaelli E, Cassulini RR, Silva DF, Clement H, Schiavon E, Zamudio FZ, et al. (February 2010). "Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels". The Journal of Biological Chemistry. 285 (6): 4130–4142. doi: 10.1074/jbc.M109.054718 . PMC   2823553 . PMID   19955179.
  11. ↑ Pan NC, Zhang T, Hu S, Liu C, Wang Y (December 2021). "Fast desensitization of acetylcholine receptors induced by a spider toxin". Channels. 15 (1): 507–515. doi:10.1080/19336950.2021.1961459. PMC   8366537 . PMID   34374321.
  12. 1 2 Suchyna TM, Tape SE, Koeppe RE, Andersen OS, Sachs F, Gottlieb PA (July 2004). "Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers". Nature. 430 (6996): 235–240. Bibcode:2004Natur.430..235S. doi:10.1038/nature02743. PMID   15241420. S2CID   4401688.
  13. ↑ Sachs F (September 2015). "Mechanical transduction by ion channels: A cautionary tale". World Journal of Neurology. 5 (3): 74–87. doi:10.5316/wjn.v5.i3.74. PMC   5221657 . PMID   28078202.
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