Exploring the link between the human microbiome and cancer development
*Context:*
/Escherichia coli/is both a commensal of the normal human gut, and the
most common causative agent of infectious disease brought about by a
Gram-negative organism. This versatility is linked to the fact that it
is able to produce a vast array of virulence factors and effectors that
manipulate different host cell functions. Recently, /E. coli/ strains
that are members of the human intestinal flora were shown to be involved
in the development of colorectal tumors in animal models of cancer.
/E. coli/strains responsible for this effect express a multi-protein
machinery, a nonribosomal peptide synthase-polyketide synthase
(NRPS-PKS) assembly line. NRPS-PKS assemblies, whose masses can reach up
to 2 megadaltons, catalyze linear reactions leading to the synthesis of
chemically diverse natural products. In this case, the machinery
synthesizes *colibactin*, a small molecule that, when secreted, leads to
targeted DNA destruction and apoptosis, genomic instability, and
colorectal tumor progression.
The objective of this project is to provide mechanistic insight into
colibactin synthesis through the structural characterization of NRPS-PKS
assemblies. We will employ biochemistry, X-ray crystallography, and
electron microscopy techniques in order to characterize different
NRPS-PKS complexes.
*Project localization:*
This project will take place at the Structural Biology Institute (IBS)
in Grenoble (France) which is part of the Partnership for Structural
Biology, providing access to different platforms including X-ray
crystallography facilities, electron microscopy, NMR, confocal
microscopy among others. This project is also supported by a
collaboration with the EM group at the IBS (G. Schoehn) and the
University of Clermont-Ferrand (R. Bonnet).
*Candidate requirement*
The candidate should have experience in recombinant protein expression,
protein purification and an interest in structural biology. The
candidate will be required to apply to the French doctoral school system
in order to obtain a scholarship for the 3-year PhD program.
Please send CV and master grades and rankings to [email protected]
<mailto:[email protected]>and [email protected]
<mailto:[email protected]>
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Pauline Macheboeuf
Institut de Biologie Structurale (UMR 5075) CEA/CNRS/UJF
Campus EPN Bâtiment IBS
71, Avenue des Martyrs
CS10090
38044 GRENOBLE CEDEX 9 FRANCE
email : [email protected]
Phone : +33 (0)4 57 42 87 53
http://www.ibs.fr/research-groups/ebev/
