2loc

From Proteopedia

Conotoxin analogue [D-Ala2]BuIIIB

PDB ID 2loc

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Structural highlights

2loc is a 1 chain structure with sequence from Conus bullatus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CM3B_CONBU Mu-conotoxins block voltage-gated sodium channels. Extremely potent inhibitor of Nav1.4/SCN4A. The inhibition is very slowly reversible.

Publication Abstract from PubMed

Among the mu-conotoxins that block vertebrate voltage-gated sodium channels (VGSCs), some have been shown to be potent analgesics following systemic administration in mice. We have determined the solution structure of a new representative of this family, mu-BuIIIB, and established its disulfide connectivities by direct mass spectrometric collision induced dissociation fragmentation of the peptide with disulfides intact. The major oxidative folding product adopts a 1-4/2-5/3-6 pattern with the following disulfide bridges: Cys5-Cys17, Cys6-Cys23, and Cys13-Cys24. The solution structure reveals that the unique N-terminal extension in mu-BuIIIB, which is also present in mu-BuIIIA and mu-BuIIIC but absent in other mu-conotoxins, forms part of a short alpha-helix encompassing Glu3 to Asn8. This helix is packed against the rest of the toxin and stabilized by the Cys5-Cys17 and Cys6-Cys23 disulfide bonds. As such, the side chain of Val1 is located close to the aromatic rings of Trp16 and His20, which are located on the canonical helix that displays several residues found to be essential for VGSC blockade in related mu-conotoxins. Mutations of residues 2 and 3 in the N-terminal extension enhanced the potency of mu-BuIIIB for NaV1.3. One analogue, [d-Ala2]BuIIIB, showed a 40-fold increase, making it the most potent peptide blocker of this channel characterized to date and thus a useful new tool with which to characterize this channel. On the basis of previous results for related mu-conotoxins, the dramatic effects of mutations at the N-terminus were unanticipated and suggest that further gains in potency might be achieved by additional modifications of this region.

Mammalian Neuronal Sodium Channel Blocker mu-Conotoxin BuIIIB Has a Structured N-Terminus That Influences Potency.,Kuang Z, Zhang MM, Gupta K, Gajewiak J, Gulyas J, Balaram P, Rivier JE, Olivera BM, Yoshikami D, Bulaj G, Norton RS ACS Chem Biol. 2013 Apr 16. PMID:23557677^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kuang Z, Zhang MM, Gupta K, Gajewiak J, Gulyas J, Balaram P, Rivier JE, Olivera BM, Yoshikami D, Bulaj G, Norton RS. Mammalian Neuronal Sodium Channel Blocker mu-Conotoxin BuIIIB Has a Structured N-Terminus That Influences Potency. ACS Chem Biol. 2013 Apr 16. PMID:23557677 doi:10.1021/cb300674x