Structure-based discovery of mitochondrial protein-protein interaction modulators of a kinase/ATP5F1 complex.

Inserm U1242 Oncogenesis, Stress, Signaling; Rennes; Sur place; EUR 5 900 - 7 100; Plein temps

Résumé du poste

Inserm U1242 Oncogenesis, Stress, Signaling in Rennes is offering a 6‑month internship focused on structure-based discovery of mitochondrial protein‑protein interaction modulators within a kinase/ATP5F1 complex. The project is part of MITOCORE and involves refining the complex model, performing MD simulations, and prioritising compounds for experimental validation.

The successful applicant will work in a multidisciplinary team with access to state-of-the-art facilities in biochemistry,

Qualifications

• We encourage applications from highly motivated Master/M2 students with a background in molecular modelling, chemoinformatics, drug discovery, structural biology or related life sciences.
• Familiarity with molecular modelling software, a Linux environment and scripting is appreciated but not required.
• On-site internship at INSERM U1242 with access to cutting-edge facilities.

Responsabilités

• Note: responsibilities are described in the project overview and include refining the structural model and running structure-based virtual screening.

Connaissances

Molecular modelling

Chemoinformatics

Drug discovery

Structural biology

Linux scripting

Formation

Master's/M2 in relevant field

Outils

GROMACS

MDAnalysis

AlphaFold3

Description du poste

Structure-based discovery of mitochondrial protein-protein interaction modulators of a kinase/ATP5F1 complex.

23/09/2026

Chemical Biology, Structural Biology, Macromolecular complexes, DNA origami, Synthetic platforms, Endoplasmic Reticulum stress, Unfolded protein response

The INSERM U1242 laboratory is a translational research structure bringing together biologists, chemists and clinicians to better understand oncogenesis in brain and gynecological cancers. By associating biologists working on cancer stress signaling pathways, chemists developing molecular tools and cancer clinicians, the laboratory aims at deciphering how tumor cells cope with stresses to resist to death and how they could be sensitized to treatments. The candidate will join an exciting and multidisciplinary scientific environment with on-site access to cutting‑edge facilities in biochemistry, biophysics, molecular biology, cell biology and structural biology. The INSERM U1242 laboratory Is affiliated to the Université of Rennes, a top French university that offers a dynamic and lively international campus with an ideal location less than 2 hours from Paris and 1 hour from Saint Malo and the beautiful Britany coast and its beaches.

Description

Supervisor: Dr X. Guillory (PI); Remuneration: 580€ net/month; Duration: 6 months between January & July 2027

Scientific background – Mitochondria produce most of the cell’s ATP through oxidative phosphorylation (OXPHOS), centered on Complex V, the mitochondrial ATP synthase. Our collaborator, Dr G. Bertolin (IGDR, UMR CNRS 6290), has shown that a particular kinase localizes inside mitochondria, where it physically and functionally interacts with the ATP5F1A and ATP5F1B subunits of Complex V to sustain ATP production and cancer cell viability. [1] Current inhibitors targeting this kinase act on the whole cellular pool of the protein and lack organelle selectivity, which drives toxicity and resistance. There is therefore a strong need for molecules that selectively disrupt the mitochondrial protein‑protein interaction (PPI) between this kinase and the ATP5F1 complex. Our group has a strong expertise in drug discovery, from in silico drug screening to in vivo evaluation, and in particular in the development of kinase inhibitors and small‑molecule PPI modulators. [2,3,4] Building on a first high‑confidence structural model of the complex obtained with AlphaFold3 and further evaluated through molecular dynamic simulations, this internship will consolidate the model and exploit it to screen for first‑in‑class modulators of this interface.

Description of the project & duties - This internship is part of MITOCORE, a collaborative program funded by the Cancéropôle Grand-Ouest, aiming to validate and pharmacologically target the kinase/ATP synthase interaction in breast cancer. You will drive the computational component of the project: refining the structural model of the complex, characterizing its druggable interface, and running a structure‑based virtual screening campaign to prioritize candidate modulators for experimental validation by our partner team.

1. 1 – Refining the structural model of the kinase/ATP5F1 interface.


2. 2 – Running and analyzing molecular dynamics simulations to assess the stability of the complex and to map druggable hot‑spots and key interface residues.


3. 3 – Performing structure‑based virtual screening of commercially available, PPI‑focused chemical libraries (e.g. ChemSpace, Fr‑PPIChem [5]).


4. 4 – Preparing a shortlist of compounds and interfacing with the experimental team for split‑FAST and biochemical validation.


5. 5 – Prioritizing candidate modulators according to predicted binding affinity, binding mode and physicochemical/ADMET properties.

If there is enough time, you will also investigate approaches to design de novo miniprotein and peptide binders (RFdiffusion, BindCraft2, etc).

Main activities and techniques involved

• Structure prediction and modelling of protein complexes (AlphaFold3, protein‑protein docking).


• Molecular dynamics simulations and trajectory analysis (GROMACS, MDAnalysis, etc).


• Analysis of protein‑protein interfaces and identification of druggable hot‑spots.


• Structure‑based virtual screening: compound library preparation, ADMET/physicochemical filtering, docking and candidate prioritisation.


• De novo design of peptides and miniproteins binders targeting the druggable interface.


• Scientific computing on HPC resources (Eskemm Data mesocentre); Linux environment and scripting ( e.g. bash; python).

Profil

Applicant profile – We encourage applications from highly motivated Master/M2 students from the national and international community, with a background in molecular modelling, chemoinformatics, drug discovery, structural biology or related life sciences, and with outstanding qualifications. Familiarity with molecular modelling software, a Linux environment and scripting is appreciated but not required.