6MK4

Solution NMR structure of spider toxin analogue [E17K]ProTx-II

Summary for 6MK4

• Entry DOI: 10.2210/pdb6mk4/pdb
• NMR Information: BMRB: 30521
• Descriptor: Beta/omega-theraphotoxin-Tp2a (1 entity in total)
• Functional Keywords: protx-ii analogue, spider toxin, peptide-membrane interactions, voltage-sensitive sodium channels, toxin
• Biological source: Thrixopelma pruriens (Peruvian green velvet tarantula)
• Total number of polymer chains: 1
• Total formula weight: 3839.75

Authors

Schroeder, C.I. (deposition date: 2018-09-25, release date: 2018-12-19, Last modification date: 2024-10-09)

Primary citation

Lawrence, N.,Wu, B.,Ligutti, J.,Cheneval, O.,Agwa, A.J.,Benfield, A.H.,Biswas, K.,Craik, D.J.,Miranda, L.P.,Henriques, S.T.,Schroeder, C.I.
Peptide-Membrane Interactions Affect the Inhibitory Potency and Selectivity of Spider Toxins ProTx-II and GpTx-1.
ACS Chem. Biol., 14:118-130, 2019

PubMed Abstract: Gating modifier toxins (GMTs) from spider venom can inhibit voltage gated sodium channels (Nas) involved in pain signal transmission, including the Na1.7 subtype. GMTs have a conserved amphipathic structure that allow them to interact with membranes and also with charged residues in regions of Na that are exposed at the cell surface. ProTx-II and GpTx-1 are GMTs able to inhibit Na1.7 with high potency, but they differ in their ability to bind to membranes and in their selectivity over other Na subtypes. To explore these differences and gain detailed information on their membrane-binding ability and how this relates to potency and selectivity, we examined previously described Na1.7 potent/selective GpTx-1 analogues and new ProTx-II analogues designed to reduce membrane binding and improve selectivity for Na1.7. Our studies reveal that the number and type of hydrophobic residues as well as how they are presented at the surface determine the affinity of ProTx-II and GpTx-1 for membranes and that altering these residues can have dramatic effects on Na inhibitory activity. We demonstrate that strong peptide-membrane interactions are not essential for inhibiting Na1.7 and propose that hydrophobic interactions instead play an important role in positioning the GMT at the membrane surface proximal to exposed Na residues, thereby affecting peptide-channel interactions. Our detailed structure-activity relationship study highlights the challenges of designing GMT-based molecules that simultaneously achieve high potency and selectivity for Na1.7, as single mutations can induce local changes in GMT structure that can have a major impact on Na-inhibitory activity.

PubMed: 30507158
DOI: 10.1021/acschembio.8b00989

Experimental method

SOLUTION NMR