PROGRAMMEDESTAGED’INITIATIONALARECHERCHE AU1ERCYCLE
SIRI
UniversitédeLyon/Universitéd’Ottawa
Appelàcandidature2017
Title
Structure-function-activityrelationshipstudiesof
enzymesfromPlasmodiumfalciparum
Supervisor-s
SurnameAGHAJARI
FirstNameNushin
[email protected]
Phone+33(0)472722633
Surname
FirstName
Email
Phone
Institute
MolecularMicrobiologyandStructuralBiology,
UMR5086CNRS-UniversityofLyon1
Lab
BiocrystallographyandStructuralBiologyof
TherapeuticTargetsGroup
Context
Plasmodiumfalciparuminducesalethalformofmalaria
causing more than 1-2 million deaths worldwide
annually, and is the world’s second biggest killer after
tuberculosis.Despiteintenseeffortsaneffectivevaccine
is still not available. Clinical treatment of this form has
becomecomplicatedbytheemergenceofdrugresistant
parasites, necessitating the development of new
antimalarialdrugs.
Through the course of its evolution, the malaria
parasite P. falciparum has developed a unique set of
biochemical pathways to adapt to the specific
environment in which it resides. While the human host
has both the de novo and salvage pathways for purine
nucleotide synthesis, the purine salvage pathway is the
Abstract/Objectives
Bibliography
sole source of purine nucleotides to the rapidly
multiplying parasite. Thus, enzymes from this pathway,
indispensable for parasite survival possess a high
druggabilityindexandconstituteidealdrugtargets.
Our lab is working on protein targets playing a role in
infectious diseases and/or cancer. We aim at
understanding the function of the given protein targets
at the molecular level, and in order to do so we use
molecular biology, biochemistry, biophysics and
structural biology. The long term goal is of course to be
able to contribute to the rational design of molecules
being able to block the unwanted action of a given
protein. Our main objective is therefore to conduct
detailed structure-function-activity relationship studies
on selected enzymes from the P. falciparum purine
nucleotide salvage pathway, followed by structureguided docking studies, chemical synthesis of ligands
(in collaboration) and in vitro screening of their
influence on enzyme activity. These first results will
leadtotheidentificationofpotentialinhibitorswhichin
turn will be evaluated for their effect on parasite
growthinculture.
The student will potentially be involved in the
molecular biology, biochemistry, biophysics and
structural biology steps, ie. he/she will participate in
theexpressionandpurificationprocessesbutalsowhen
adequate in the biochemical characterization, and the
structural biology studies of these targets. As concerns
the later, focus will be given on the x-ray
crystallographystudies.
- BallutL.,ViolotS.,ShivakumaraswamyS.,Thota
LP.,SathyaM.,KunalaJ.,DijkstraBW.,TerreuxR.,
HaserR.,BalaramH.,&AghajariN.(2015)Active
sitecouplinginPlasmodiumfalciparumGMP
synthetaseistriggeredbydomainrotation.
NatureComm.6:8930,DOI:
10.1038/ncomms9930.
- Marton Z.,GuillonR.,KrimmI.,Preeti,Rahimova
R.,EgronD.,JordheimLP.,AghajariN.,Dumontet
C.,PérigaudC.,LionneC.,PeyrottesS.&ChaloinL.
(2015)IdentificationofNoncompetitive
InhibitorsofCytosolic5'-NucleotidaseIIUsinga
Fragment-BasedApproach.J.Med.Chem.
58(24):9680-96.doi:
10.1021/acs.jmedchem.5b01616.
- LipskiA.,WatzlawickH.,RavaudS.,RobertX.,
RhimiM.,HaserR.,MattesR.&AghajariN.(2013)
-
Mutationsinducinganactivesiteapertureof
Rhizobiumsp.sucroseisomeraseconfer
hydrolyticactivity.ActaCryst.D.Biological
Crystallography.69:298-307.
JordheimL.P.,MartonZ.,RhimiM.,Cros-Perrial
E.,LionneC.,PeyrottesS.,DumontetC.,Aghajari
N.&ChaloinL.(2013)Identificationand
characterizationofinhibitorsofcytoplasmic5'nucleotidasecN-IIissuedfromvirtualscreening.
Biochem.Pharmacol. 85(4):497-506.
Location
Duration
Language
(French/English/Both)
MolecularMicrobiologyandStructuralBiochemistry,
UMR5086CNRS-UniversityofLyon1
InstitutefortheBiologyandChemistryofProteins,
UMS3760
7passageduVercors,F-69367LyonCedex07,France
3months
Both