Conus
peptides, biodiversity-based discovery and exogenomics
The 700 different predatory cone snails (genus Conus)
have evolved complex venoms, each species with it's own
distinct set of 100 to 200 biologically active venom peptides.
These are specified by a small number of gene superfamilies
that rapidly diversify as speciation occurs. Most conopeptides
are multiply disulfide cross-linked, with peptides in a
superfamily having a characteristic disulfide framework,
resulting in generally similar structures, but diverging
function. Conopeptides have direct therapeutic applications
- at least five are in clinical trials, and one (Prialt)
has been approved as a drug for severe pain. Many conopeptides
have exquisite targeting selectivity, and have the potential
to be diagnostic ligands for a particular molecular isoform
of an ion channel or receptor (the majority of conopeptide
targets fall into these categories). The rapid diversification
observed in conopeptide genes may be a general feature of
all genes used by organisms to interact with other organisms
in their environment. Across megadiverse taxa, each individual
species has it's own complement of predators, prey and competitors;
those genes whose products are used to mediate the biotic
interactions of that particular species should thus be rapidly
diversifying, if compared to homologous genes of other species.
For conopeptides, an integrated approach to discovery that
incorporates phylogenetics has been highly successful for
identifying peptides with differing subtype-specificity. Olivera BM. J Biol Chem. 2006
Aug 11; [Epub ahead of print]
Phylogenetic tree. The relationship of C. magus to other
species is shown in the phylogenetic tree based on 16S
sequences. The red branches show species in the subgenus
Pionoconus, the purple branch is a
fish-hunter in Chelyconus. The green branch shows a mollusc
hunter (C. aulicus). The uncolored branches are worm-hunting
species, that specialize on amphinomid polychaetes; these
express α-conopeptides in the α4/3 subfamily.
Baldomero M. Olivera. JBC
Papers in Press. Published on August 11, 2006 as Manuscript
R600020200
Baldomero M. Olivera. JBC Papers in Press. Published on
August 11, 2006 as Manuscript R600020200
Baldomero M. Olivera. JBC Papers in Press. Published on
August 11, 2006 as Manuscript R600020200
Talley T.T., et al. JBC Papers in Press. Published on
June 27, 2006 as Manuscript M602969200
α-Conotoxin OmIA binding to
AChBP. Concentration response curves were determined for
α-
conotoxin OmIA displacement of radioligand binding to
AChBP from Lymnaea stagnalis and Aplysia
californica as described in Experimental Procedures. A,
competition with [125I] α-bungarotoxin. B,
competition with [3H] epibatidine. Calculated Kds are
shown in Table I. n = 6 for all experiments. Talley T.T., et al. JBC Papers
in Press. Published on June 27, 2006 as Manuscript M602969200
