GsMTx-4

From WikiProjectMed
Jump to navigation Jump to search
M-theraphotoxin-Gr1a
Identifiers
OrganismGrammostola rosea
SymbolGsMTx-4
PDB1LU8
UniProtQ7YT39
Search for
StructuresSwiss-model
DomainsInterPro
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)
  • 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]

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
KD IC50
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]

References

  1. ^ a b c 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. ^ a b 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. ^ a b 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. ^ a b c d 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. ^ a b c 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. ^ a b 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. ^ a b c d 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. ^ a b 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.
Retrieved from "https://mdwiki.org/wiki/GsMTx-4"