Mosquito © Steluma / Flick, CC BY-NC
Mosquito © Steluma / Flick, CC BY-NC
The structure of the BinAB toxin discovered: one small step for Man ... one giant problem for mosquitoes!
What if we could get rid of mosquitoes without polluting the environment? It can be done! Produced in crystal form by a bacterium, the BinAB toxin specifically kills the larvae of Culex and Anopheles mosquitoes, but it has no effect on Asian tiger mosquitoes (or Aedes), vectors of Dengue fever and Chikungunya. To expand the toxin's spectrum of action, we need to understand its molecular structure – something which has eluded us for a long time, but which has now been published in the 28 September 2016 issue of the journal Nature by an international consortium of researchers in which scientists from the Institut de biologie structurale (CNRS/CEA/Université Grenoble Alpes) were involved.
Mosquitoes are vectors for a number of devastating diseases, including malaria (spread by Anopheles mosquitoes) and filariasis (spread by Culex mosquitoes). Produced in nanocrystal form by the bacterium Bacillus sphaericus, the BinAB toxin specifically kills the larvae of both these mosquito groups. Behind the environmental safety of the BinAB toxin, which is harmless to other insects, crustaceans and humans, is a complex five-stage intoxication process (see text box opposite). As such, BinAB is used across many countries to help keep mosquito populations in check.

Unfortunately, the strength of the BinAB toxin is also its Achilles' heel: it is ineffective against the larvae of Aedes mosquitoes, which carry the Dengue, Zika and Chikungunya viruses. One way of extending BinAB's spectrum of action could be to remodel it, but we need to understand its structure to do this. X-ray crystallography is a highly effective method for revealing a protein's structure, but it is typically only used with large crystals, measuring around a tenth of a millimetre. BinAB nanocrystals that form in vivo only measure a few ten-thousandths of a millimetre and, once dissolved, the toxin does not recrystallise.

An international consortium of scientists headed up by Jacques-Philippe Colletier, CNRS scientist at the Institut de biologie structurale (CNRS/CEA/Université Grenoble Alpes), Brian Federici, Professor at the University of California, Riverside (UCR) and David Eisenberg, Professor at the University of California, Los Angeles (UCLA), has just published their findings about this structure, which they cracked by working with natural nanocrystals.

To tackle the small size of the crystals, they used a new type of X-ray source, a free-electron laser, with the advantage that it can deliver ultra-short but very intense X-ray pulses. The fact that the structure of BinAB was a complete mystery meant that a purely experimental (de novo) approach had to be adopted – which had so far only been used on test samples where the structure was already known, in order to prove that it would work.

In this way, the structure of BinAB is the first to have been uncovered using such small crystals AND de novo phasing in a free-electron laser. The idea of solving structures from smaller and more complex natural assemblages, such as the tiny specialised structures within cells known as organelles, now does not seem so far-fetched.

In the nearer term, this breakthrough in our understanding of BinAB's structure can be used to expand its spectrum of action, with a view to developing a "three-in-one" toxin that targets the larvae of all three types of mosquito: Aedes (to curb the spread of the Zika virus in particular), Culex (the vector for filariasis) and Anopheles (the vector for malaria).

C’est à partir de ces cristaux (observés en microscopie électronique à balayage, à gauche) que la structure de la toxine BinAB a été résolue (schéma, à droite). © Mari Gingery (cliché de microscopie électronique, à gauche) / Jacques-Philippe Colletier (sc

The mystery surrounding the structure of the BinAB toxin (right) was solved using these crystals (seen through a scanning electron microscope, left).
© Mari Gingery (electron microscope image, left) / Jacques-Philippe Colletier (image, right)

Published on January 4, 2017
Updated on January 4, 2017