De novo phasing with X-ray laser reveals mosquito larvicide BinAB structure

Jacques Philippe Colletier, Michael R. Sawaya, Mari Gingery, Jose A. Rodriguez, Duilio Cascio, Aaron S. Brewster, Tara Michels-Clark, Robert H. Hice, Nicolas Coquelle, Sébastien Boutet, Garth J. Williams, Marc Messerschmidt, Daniel P. DePonte, Raymond G. Sierra, Hartawan Laksmono, Jason E. Koglin, Mark S. Hunter, Hyun Woo Park, Monarin Uervirojnangkoorn, Dennis K. BideshiAxel T. Brunger, Brian A. Federici, Nicholas K. Sauter, David S. Eisenberg

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

BinAB is a naturally occurring paracrystalline larvicide distributed worldwide to combat the devastating diseases borne by mosquitoes. These crystals are composed of homologous molecules, BinA and BinB, which play distinct roles in the multi-step intoxication process, transforming from harmless, robust crystals, to soluble protoxin heterodimers, to internalized mature toxin, and finally to toxic oligomeric pores. The small size of the crystals - 50 unit cells per edge, on average - has impeded structural characterization by conventional means. Here we report the structure of Lysinibacillus sphaericus BinAB solved de novo by serial-femtosecond crystallography at an X-ray free-electron laser. The structure reveals tyrosine- and carboxylate-mediated contacts acting as pH switches to release soluble protoxin in the alkaline larval midgut. An enormous heterodimeric interface appears to be responsible for anchoring BinA to receptor-bound BinB for co-internalization. Remarkably, this interface is largely composed of propeptides, suggesting that proteolytic maturation would trigger dissociation of the heterodimer and progression to pore formation.

Original languageEnglish (US)
Pages (from-to)43-47
Number of pages5
JournalNature
Volume539
Issue number7627
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Colletier, J. P., Sawaya, M. R., Gingery, M., Rodriguez, J. A., Cascio, D., Brewster, A. S., Michels-Clark, T., Hice, R. H., Coquelle, N., Boutet, S., Williams, G. J., Messerschmidt, M., DePonte, D. P., Sierra, R. G., Laksmono, H., Koglin, J. E., Hunter, M. S., Park, H. W., Uervirojnangkoorn, M., ... Eisenberg, D. S. (2016). De novo phasing with X-ray laser reveals mosquito larvicide BinAB structure. Nature, 539(7627), 43-47. https://doi.org/10.1038/nature19825