Team
Structural Biology of Novel Targets in Human Diseases

Dpt: Signaling through Chromatin

Our research activities

Our research group uses an integrated structural biology and biophysical approach combined with functional studies to understand the inhibition mechanisms of novel protein and RNA targets involved in human diseases with the aim of developing novel therapeutics. In collaboration with teams in academia and industry, we are improving the potency and selectivity of inhibitors with biomedical applications.
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Andrés PALENCIA

PhD, HDR and Team Leader

04 76 54 95 75

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Our research axes

We are using an integrative structural biology approach to provide insights into biological systems by combining the structural snapshots provided by X-ray crystallography and Cryo-electron microscopy with the information on dynamics provided by solution NMR spectroscopy.

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These proteins are responsible for attaching the correct amino acid to the cognate tRNA (aminoacylation); and preventing mischarging of tRNAs to non-correct amino acids (editing). AARSs are interesting therapeutic targets as they are key for protein translation, and present differences between microbes and humans that we are exploiting for drug discovery.

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In eukaryotes, 3’ pre-mRNA processing occurs via the concerted action of a large complexes that cleave the 3’-end of unmatured mRNAs before the addition (or not) of the poly-A tail and export to the cytoplasm for translation. As these processes are deregulated in human diseases, we investigate the targeting of key proteins for therapeutic applications, notably in cancer, but also in infectious diseases.

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Transcription by RNA polymerase III yields precursor tRNAs containing 3’ sequences (trailer) and 5’ sequences (leader) that need to be cleaved off. We investigate the molecular mechanisms leading to the maturation of eukaryotic 3’-end tRNAs, a process that is deregulated in several human diseases.

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Our major publications

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Adenosine Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase

Hoffmann, G., Le Gorrec, M., Mestdach, E., Cusack, S., Salmon, L., *Jensen, MR. & *Palencia,…

Journal of The American Chemical Society 2023 145(2), 800-810. *Corresponding authors

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Human Histone pre-mRNA Assembles Histone- or Canonical-mRNA Processing Complexes by Overlapping 3’-End Sequence Elements

Ielasi, F.S., Ternifi, S., Fontaine, E., Iuso, D., Couté, Y. & *Palencia A.

Nucleic Acids Research 2022 28; 50 (21):12425-12443

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Visualizing protein breathing motions associated with aromatic ring flipping

Mariño Perez, L., Ielasi, FS., Bessa, LM., Maurin, D., Kragelj, J., Blackledge, M., Salvi, N.,…

Nature 2022 602, 695-700. *Corresponding authors

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Aminoacyl-tRNA synthetases as drug targets

Lukarska, M. & *Palencia, A.

The Enzymes, Elsevier. 2020 48:321-350

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Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection

Swale, C., Bougdour, A., Gnahoui-David, A., Tottey, J., Georgeault, S., *Laurent,  F., *†Palencia, A.  *†Hakimi, M.A.

Science Trans. Medicine 2019 6;11(517). †Equally contributing authors

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Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis

*†Palencia, A., †*Bougdour, A., et al. 

EMBO Molecular Medicine 2017 9: 385-394 . Highlighted in  France 3 news. *Corresponding Authors.

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Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase

Palencia*, A., Li, X., Bu, W., Ding, C., Easom, E., Feng, et al.

Antimicrobial agents and chemotherapy 2016 60(10):6271-80

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Structural characterisation of antibiotic self-immunity tRNA synthetase in plant tumour biocontrol agent.

Chopra, S.†, Palencia, A.†, et al.

Nature comm 2016 7:12928 †Joint-First Authors

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Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase

†Chopra, S., †Palencia, A., et al. 

Nature comm 2013 4, 1417. †Joint-First Authors.

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Structural dynamics of the aminoacylation and proofreading functional cycle of bacterial leucyl-tRNA synthetase

Palencia, A., Crepin, T., et al.

Nature Struct. & Mol. Biol 2012 19, 677-84.

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Our activities in pictures

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Our collaborations

  • Malene Jensen, IBS, Grenoble, France
  • Rolf Müller, Helmholtz Institute, Saarbrücken, Germany
  • Paul Finn, Oxford Drug Design, Oxford, UK
  • Philip Rosenthal, UCSF, San Francisco, USA
  • Vincent Cattoir, Inserm U1230, CHU Rennes, France
  • Wojtek Galej, EMBL, Grenoble, France

Our technologies

  • Integrative Structural Biology Approach
  • Production of RNAs, and Proteins in Bacteria, Insect Cells, and Mammalian Systems
  • Crystallization of Proteins, RNAs, and Inhibitors (small molecules, peptides …)
  • X-ray Crystallography, NMR and (Cryo) Electron Microscopy
  • Biophysical Methods to Guide Drug Discovery and Hit Optimisation
  • In Silico Approaches for the Identification of De Novo Inhibitors