Structural Microbiology and Biodesign lab


We study the three-dimensional structure of essential components of living matter in order to arrive at an atomic resolution understanding of the architecture and molecular mechanisms of life. We focus on the investigation of the molecular bases of the activity of proteins relevant to bacterial fitness, in particular in signal transduction pathways in pathogenic bacteria. These systems evolved to mediate the adaptation of bacterial physiology to the host environment and survival against the immune system. Thus, we aim to understand how protein:protein interfaces (co)evolve to mediate information flow in bacteria and serve as a driving force in the evolution of life. We employ interdisciplinary approaches, integrating structural biology, biochemistry, and protein biophysics, along with computational approaches and in vivo assays.

Research Lines

Molecular mechanisms of the regulation of nitrogen metabolism in Actinobacteria

We have contributed to demonstrate that in diverse actinobacteria nitrogen metabolism is regulated by the signaling pathway that involves the protein kinase PknG. Both in the pathogen that causes tuberculosis in humans and in free-living species used in biotechnological processes, PknG controls the intracellular levels of glutamate in response the amino acids present in the medium. Notably, the integrity of this signal transduction pathway is critical for the virulence of Koch's bacillus. In Mycobacterium, the GarA regulator modulates by direct interaction three metabolic enzymes, including a large glutamate dehydrogenase (L-GDH). This causes alpha-ketoglutarate to deviate from the Krebs cycle in favor of glutamate synthesis; instead, phosphorylation of GarA by PknG inhibits the action of the regulator and alpha-ketoglutarate is then directed to the Krebs cycle. We recently elucidated the 3D structure of the mycobacterial L-GDH modulated by GarA. These findings revealed unique aspects of the architecture of this enzyme type and suggest interesting regulatory mechanisms. A deep understanding of the molecular mechanisms involved in this signaling pathway will allow deciphering how M. tuberculosis and other actinobacteria modulate their metabolism and other key physiological processes. This will contribute to the design of drugs against tuberculosis and biotechnological innovations.


Technological services are provided through the Argentine Platform for Structural Biology and Metabolomics PLABEM.

Selected Publications

  • 3D architecture and structural flexibility revealed in the subfamily of large glutamate dehydrogenases by a mycobacterial enzyme. Communications Biology 4, 684. Lázaro, M., Melero, R., Huet, C., López-Alonso, J.P., Delgado, S., Dodu, A., Bruch, E.M., Abriata, L.A., Alzari, P.M., Valle, M. and Lisa, M.N. (2021).
  • A Tetratricopeptide Repeat Scaffold Couples Signal Detection to OdhI Phosphorylation in Metabolic Control by the Protein Kinase PknG. mBio 12, e0171721. Lisa, M.N., Sogues, A., Barilone, N., Baumgart, M., Gil, M., Graña, M., Durán, R., Biondi, R., Bellinzoni, M., Bott, M., Alzari, P.M. (2021).
  • PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis. PLoS Pathogens 13, e1006399. Rieck, B., Degiacomi, G., Zimmermann, M., Cascioferro, A., Boldrin, F., Lazar-Adler, N.R., Bottrill, A.R., le Chevalier, F., Frigui, W., Bellinzoni, M., Lisa, M.N., Alzari, P.M., Nguyen, L., Brosch, R., Sauer, U., Manganelli, R. and O’Hare, H. (2017).
  • Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis. Structure 23, 1039-1048. Lisa, M.N., Gil, M., André-Leroux, G., Barilone, N., Durán, R., Biondi, R.M. and Alzari, P.M. (2015).

For a complete list, check my

TW: @MaNataliaLisa