5WE3

Solution NMR structure of PaurTx-3

Summary for 5WE3

• Entry DOI: 10.2210/pdb5we3/pdb
• NMR Information: BMRB: 30317
• Descriptor: Beta-theraphotoxin-Ps1a (1 entity in total)
• Functional Keywords: disulfide rich peptides, pain, rational drug design, serum stability, spider venom, voltage-gated ion channels, trimolecular complex, toxin
• Biological source: Paraphysa scrofa (Chilean copper tarantula)
• Total number of polymer chains: 1
• Total formula weight: 4072.82

Authors

Agwa, A.J.,Schroeder, C.I. (deposition date: 2017-07-06, release date: 2017-09-13, Last modification date: 2024-11-20)

Primary citation

Agwa, A.J.,Huang, Y.H.,Craik, D.J.,Henriques, S.T.,Schroeder, C.I.
Lengths of the C-Terminus and Interconnecting Loops Impact Stability of Spider-Derived Gating Modifier Toxins.
Toxins (Basel), 9:-, 2017

PubMed Abstract: Spider gating modifier toxins (GMTs) are potent modulators of voltage-gated ion channels and have thus attracted attention as drug leads for several pathophysiological conditions. GMTs contain three disulfide bonds organized in an inhibitory cystine knot, which putatively confers them with high stability; however, thus far, there has not been a focused study to establish the stability of GMTs in physiological conditions. We examined the resistance of five GMTs including GpTx-1, HnTx-IV, HwTx-IV, PaurTx-3 and SgTx-1, to pH, thermal and proteolytic degradation. The peptides were stable under physiological conditions, except SgTx-1, which was susceptible to proteolysis, probably due to a longer C-terminus compared to the other peptides. In non-physiological conditions, the five peptides withstood chaotropic degradation, and all but SgTx-1 remained intact after prolonged exposure to high temperature; however, the peptides were degraded in strongly alkaline solutions. GpTx-1 and PaurTx-3 were more resistant to basic hydrolysis than HnTx-IV, HwTx-IV and SgTx-1, probably because a shorter interconnecting loop 3 on GpTx-1 and PaurTx-3 may stabilize interactions between the C-terminus and the hydrophobic patch. Here, we establish that most GMTs are exceptionally stable, and propose that, in the design of GMT-based therapeutics, stability can be enhanced by optimizing the C-terminus in terms of length, and increased interactions with the hydrophobic patch.

PubMed: 28805686
DOI: 10.3390/toxins9080248

Experimental method

SOLUTION NMR