5TCZ

NMR solution structure of engineered Protoxin-II analog

Summary for 5TCZ

• Entry DOI: 10.2210/pdb5tcz/pdb
• NMR Information: BMRB: 30181
• Descriptor: Beta/omega-theraphotoxin-Tp2a (1 entity in total)
• Functional Keywords: venom peptide analog, inhibitor, cystine knot, toxin
• Biological source: Thrixopelma pruriens (Peruvian green velvet tarantula)
• Total number of polymer chains: 1
• Total formula weight: 3862.72

Authors

Gibbs, A.C.,Wickenden, A.D. (deposition date: 2016-09-16, release date: 2017-01-18, Last modification date: 2024-10-23)

Primary citation

Flinspach, M.,Xu, Q.,Piekarz, A.D.,Fellows, R.,Hagan, R.,Gibbs, A.,Liu, Y.,Neff, R.A.,Freedman, J.,Eckert, W.A.,Zhou, M.,Bonesteel, R.,Pennington, M.W.,Eddinger, K.A.,Yaksh, T.L.,Hunter, M.,Swanson, R.V.,Wickenden, A.D.
Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor.
Sci Rep, 7:39662-39662, 2017

PubMed Abstract: Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.

PubMed: 28045073
DOI: 10.1038/srep39662

Experimental method

SOLUTION NMR