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. Bideshi, Axel T. Brunger, Brian A. Federici, Nicholas K. Sauter and David S. Eisenberg ()
Additional contact information
Jacques-Philippe Colletier: Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS
Michael R. Sawaya: UCLA-DOE Institute for Genomics and Proteomics, University of California
Mari Gingery: UCLA-DOE Institute for Genomics and Proteomics, University of California
Jose A. Rodriguez: UCLA-DOE Institute for Genomics and Proteomics, University of California
Duilio Cascio: UCLA-DOE Institute for Genomics and Proteomics, University of California
Aaron S. Brewster: Lawrence Berkeley National Laboratory
Tara Michels-Clark: Lawrence Berkeley National Laboratory
Robert H. Hice: Molecular and Developmental Biology, University of California
Nicolas Coquelle: Institut de Biologie Structurale (IBS), Univ. Grenoble Alpes, CEA, CNRS
Sébastien Boutet: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Garth J. Williams: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Marc Messerschmidt: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Daniel P. DePonte: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Raymond G. Sierra: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Hartawan Laksmono: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Jason E. Koglin: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Mark S. Hunter: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Hyun-Woo Park: Molecular and Developmental Biology, University of California
Monarin Uervirojnangkoorn: Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University
Dennis K. Bideshi: Molecular and Developmental Biology, University of California
Axel T. Brunger: Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University
Brian A. Federici: Molecular and Developmental Biology, University of California
Nicholas K. Sauter: Lawrence Berkeley National Laboratory
David S. Eisenberg: UCLA-DOE Institute for Genomics and Proteomics, University of California

Nature, 2016, vol. 539, issue 7627, 43-47

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19825

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