PMID- 23760503
OWN - NLM
STAT- MEDLINE
DCOM- 20131021
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 31
DP  - 2013 Aug 2
TI  - Analysis of the structural and molecular basis of voltage-sensitive sodium 
      channel inhibition by the spider toxin huwentoxin-IV (mu-TRTX-Hh2a).
PG  - 22707-20
LID - 10.1074/jbc.M113.461392 [doi]
AB  - Voltage-gated sodium channels (VGSCs) are essential to the normal function of the 
      vertebrate nervous system. Aberrant function of VGSCs underlies a variety of 
      disorders, including epilepsy, arrhythmia, and pain. A large number of animal 
      toxins target these ion channels and may have significant therapeutic potential. 
      Most of these toxins, however, have not been characterized in detail. Here, by 
      combining patch clamp electrophysiology and radioligand binding studies with 
      peptide mutagenesis, NMR structure determination, and molecular modeling, we have 
      revealed key molecular determinants of the interaction between the tarantula 
      toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV 
      residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important 
      for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and 
      NMR studies indicated that folding was normal for several key mutants, suggesting 
      that these amino acids probably make specific interactions with sodium channel 
      residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and 
      K27A) that are involved in isoform-specific VGSC interactions. Our structural and 
      functional data were used to model the docking of huwentoxin-IV into the domain 
      II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed 
      of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove 
      formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight 
      into the structural and molecular basis of sodium channel block by huwentoxin-IV 
      and may provide a basis for the rational design of toxin-based peptides with 
      improved VGSC potency and/or selectivity.
FAU - Minassian, Natali A
AU  - Minassian NA
AD  - Department of Neuroscience Discovery, Janssen Research & Development, LLC, San 
      Diego, California 92121, USA.
FAU - Gibbs, Alan
AU  - Gibbs A
FAU - Shih, Amy Y
AU  - Shih AY
FAU - Liu, Yi
AU  - Liu Y
FAU - Neff, Robert A
AU  - Neff RA
FAU - Sutton, Steven W
AU  - Sutton SW
FAU - Mirzadegan, Tara
AU  - Mirzadegan T
FAU - Connor, Judith
AU  - Connor J
FAU - Fellows, Ross
AU  - Fellows R
FAU - Husovsky, Matthew
AU  - Husovsky M
FAU - Nelson, Serena
AU  - Nelson S
FAU - Hunter, Michael J
AU  - Hunter MJ
FAU - Flinspach, Mack
AU  - Flinspach M
FAU - Wickenden, Alan D
AU  - Wickenden AD
LA  - eng
SI  - PDB/2M4X
SI  - PDB/2M4Z
SI  - PDB/2M50
PT  - Journal Article
DEP - 20130612
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Sodium Channel Blockers)
RN  - 0 (Spider Venoms)
RN  - 0 (huwentoxin IV, Selenocosmia huwena)
SB  - IM
MH  - Amino Acid Sequence
MH  - HEK293 Cells
MH  - Humans
MH  - *Ion Channel Gating
MH  - Magnetic Resonance Spectroscopy
MH  - Molecular Dynamics Simulation
MH  - Molecular Sequence Data
MH  - Radioligand Assay
MH  - Sequence Homology, Amino Acid
MH  - Sodium Channel Blockers/*pharmacology
MH  - Spider Venoms/*chemistry/pharmacology
MH  - Structure-Activity Relationship
PMC - PMC3829356
OTO - NOTNLM
OT  - Electrophysiology
OT  - Ion Channels
OT  - Sodium Channels
OT  - Structural Biology
OT  - Toxins
EDAT- 2013/06/14 06:00
MHDA- 2013/10/22 06:00
PMCR- 2014/08/02
CRDT- 2013/06/14 06:00
PHST- 2013/06/14 06:00 [entrez]
PHST- 2013/06/14 06:00 [pubmed]
PHST- 2013/10/22 06:00 [medline]
PHST- 2014/08/02 00:00 [pmc-release]
AID - S0021-9258(20)45432-8 [pii]
AID - M113.461392 [pii]
AID - 10.1074/jbc.M113.461392 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Aug 2;288(31):22707-20. doi: 10.1074/jbc.M113.461392. Epub 2013 
      Jun 12.