Installé dans l’appartement où Louis Pasteur passa les sept dernières années de sa vie, le musée Pasteur constitue une occasion unique de pénétrer dans l’univers de l’illustre savant : de visualiser sa vie au quotidien aux côtés de son épouse et de traverser son œuvre scientifique abondante.
Faire un don à l’Institut Pasteur, c’est contribuer aux avancées de ses recherches biomédicales et être ainsi associé à ses chercheurs et à leurs découvertes sur les cancers, les maladies du cerveau, les maladies infectieuses, et bien d’autres encore…
La stratégie scientifique de l’Institut Pasteur s’appuie sur le développement de thématiques originales et innovantes, encourageant les échanges et la pluridisciplinarité des approches de recherche. Pour relever ce défi, l’Institut Pasteur met à la disposition de ses équipes les ressources technologiques indispensables à leur réactivité et à une recherche de haut niveau.
Le Centre médical de l’Institut Pasteur est un centre de santé conventionné secteur 1. Il propose une offre de soin à destination des voyageurs, et la prise en charge diagnostique et thérapeutique des maladies infectieuses, tropicales et allergiques. Le Centre médical de l’Institut Pasteur, engagé depuis 2008 dans la mise en place d’une démarche Qualité, est le premier centre de santé français à recevoir en janvier 2011 la certification qualité "AFAQ Centre de santé" de l'AFNOR Certification.
Depuis la création du premier cours de « microbie technique » en 1889, l’enseignement reste une priorité pour l’Institut Pasteur. Reconnu au niveau international, la qualité de l’enseignement de l’Institut Pasteur lui permet d’accueillir chaque année des étudiants venus du monde entier pour parfaire leur formation ou compléter leur cursus.
Doctoral school affiliation and University: ‘Interdisciplinaire pour le Vivant’ (iViv, ED387), Université ‘Pierre et Marie Curie’
Presentation of the laboratory and its research topics:
The Structural Microbiology Unit at the Institut Pasteur has a long-lasting interest in the structural biology of mycobacteria and has been active member, for more than ten years, of three successive European Commission-funded clusters dedicated to the identification, characterization and validation of new targets for anti-tuberculosis drug development, i.e. the projects ‘X-TB’ (2001-2005), ‘NM4TB’ (2006-2011) and the ongoing project ‘More Medicines for TB’ (‘MM4TB’, 2011-2016), all led by Prof. Stewart T. Cole (EPFL, Lausanne, Switzerland). The activity of the lab has been focused on signal transduction mechanisms ranging from two component systems to Ser/Thr kinases, key signalling elements in Mycobacterium tuberculosis. Our recent work revealed that central metabolism in mycobacteria is controlled by the Ser/Thr kinase PknG (one of the most studied kinases in M. tuberculosis) through GarA, a small FHA-domain protein that regulates the activity of the enzymes situated at the a-ketoglutarate branching point, a crucial crossroad between carbon and nitrogen metabolism.
The project below has recently been selected for funding by the ANR through a ‘Young researcher’ grant to M. Bellinzoni.
Description of the project:
Tuberculosis remains nowadays a major threat for public health, with approximately one third of the world population estimated to be latently infected with Mycobacterium tuberculosis, according to the WHO  and therefore susceptible to develop active disease at anytime through reactivation, especially in case of weakening of the immune response. To become able to target this huge reservoir in an effective way would constitute undoubtedly a great progress towards the eradication of the disease. Indeed, one of the biggest challenges in drug development against tuberculosis is how to hit dormant bacteria, a particularly difficult task in light of the fact that the molecular mechanisms underlying the adaptation of the pathogen to the different environmental conditions during the disease stages, notably dormancy, are still poorly understood. For these reasons we have been actively involved in the study of how M. tuberculosis controls its central metabolism, a critical process in order to switch between active growth and dormancy. Our recent work in this field has been focused on the structural characterization of a-ketoglutarate decarboxylase (KGD), a central enzyme in the tricarboxylic acid cycle (TCA) and part of the tripartite a-ketoglutarate dehydrogenase complex (KDH). First identified as an enzyme inhibited by GarA , an FHA-domain protein acting in turn as a sort of molecular switch controlled by phosphorylation, we showed that KGD is an extremely dynamic object able to carry out different reactions depending on the acyl acceptor substrate , and that its inhibition by GarA takes place through an unprecedented allosteric mechanism, by which the enzyme is frozen into a catalytically incompetent state .
Although the KDH complex was initially reported to be absent in M. tuberculosis due to failure to detect its activity , we now know that not only this activity can be measured under appropriate conditions , but also that this complex may in reality form a unique ‘supercomplex’ with pyruvate dehydrogenase (PDH), a similarly structured complex involved in the oxidative decarboxylation of pyruvate produced by glycolysis. Indeed, both complexes are known to be huge molecular assemblies structured around a central core, made of either 24 or 60 subunits of the E2 component, and recent data support the existence of such a hybrid supercomplex in Corynebacterium glutamicum . Merging the two complexes would generate a MDa-range multienzyme assembly that could span a diameter larger than the ribosome and without analogies in other organisms. The objective of this project is first to validate the existence of this supercomplex as a physiologically relevant enzymatic machinery in the Corynebacterineae suborder, working on the non-pathogenic species C. glutamicum and M. smegmatis, then to purify and characterize it by a combination of hybrid structural biology approaches, notably cryo-electron microscopy (on the newly installed facilities at the Institut Pasteur), to get a three-dimensional model of this supramolecular biological object. The ultimate goal, however, is to go beyond a static structural picture, clarifying the dynamic processes by which the different enzymatic activities may be temporally and spatially coordinated, and to understand, in the end, by which molecular mechanisms (and in response to which stimuli) such a huge machinery could be regulated.
The candidate should have a strong interest in structural biology and willing to learn and take advantage of working with multiple techniques (e.g. cryo-electron microscopy, X-ray crystallography, SAXS) and cutting-edge equipment. Some prior experience in any of these methods, as well as in protein purification would be an asset.