Biomolecular Structure

 

Previous Research Results:

We focus our research on protein structure and function, with a particular emphasis on enzymes with potential biomedical implications. Using X-ray crystallography as the main technical approach, complemented by a plethora of other biochemical, biophysical, and computational techniques, we try to understand the function of macromolecules and macromolecular complexes from their high-resolution structures. We are currently interested in the characterization and validation of potential drug targets from bacterial human pathogens and in elucidating the molecular details of specific coagulation factor IIa recognition and inhibition by natural macromolecular anticoagulants from haematophagous parasites.

In this context, we have recently determined the three-dimensional structure of a novel glucosyl-3-phosphoglycerate synthase from Mycobacterium tuberculosis, which integrates an essential and unique pathway of this human pathogen. Together with the structure of the closely related mannosyl-3-phosphoglycerate synthase from the hyperthermophile Rubrobacter xylanophilus, this structure revealed the molecular determinants of substrate specificity and established a knowledge base for the rational design of specific inhibitors. In a similar line, we have determined the three-dimensional structure of human thrombin in complex with three small synthetic inhibitors, unveiling important details of their specific mode of action.

 

Biomolecular Structure - Top (a) and side (b) view of the experimental three-dimensional model of the decameric cytosolic glutamine synthetase from the model legume Medicago truncatula.

IMAGE: Top (a) and side (b) view of the experimental three-dimensional model of the decameric cytosolic glutamine synthetase from the model legume Medicago truncatula (Torreira et al. (2014) Acta Crystallographica D70, 981-993).

 

Future Research:

The recent uprising of life-threatening infectious diseases of bacterial origin, brought about by the increasing resistance of many pathogens to the available antibiotics, prompts for the functional and molecular characterization of novel pathways that are amenable to therapeutic intervention. Our group will therefore continue the molecular and structural dissection of the unique M. tuberculosis pathways that lead to cell wall synthesis, in order to identify and validate suitable drug targets.

Coagulation disorders are other life-threatening and highly incapacitating pathologies for which more efficient and safer therapies are much needed. By pursuing the characterization of the structural determinants of thrombin recognition by natural macromolecular anticoagulants, we will contribute towards the development of better antithrombotic drugs.

In summary, our group will carry on with the structural and biochemical characterization of medically relevant enzymes and drug targets from human pathogens and of unique natural anticoagulants from haematophagous animals, ultimately envisaging the development of novel therapeutic strategies.

 

Selected References:

Pereira, P.J.B.; Bergner, A.; Macedo-Ribeiro, S.; Huber, R.; Matschiner, G.; Fritz, H.; Sommerhoff, C.P.; Bode, W. (1998) Human beta-tryptase is a ring-like tetramer with active sites facing a central pore. Nature 392, 306-311.

Pereira, P. J. B.; Macedo-Ribeiro, S.; Parraga, A.; Perez-Luque, R.; Cunningham, O.; Darcy, K.; Mantle, T. J.; Coll, M. (2001) Structure of human biliverdin IX-b reductase, an early fetal bilirubin IX-b producing enzyme. Nature Structural Biology 8, 215-220.

Rocha, R; Pereira, P.J.B.; Santos, M.A.S.; Macedo-Ribeiro, S. (2011) Unveiling the structural basis for translational ambiguity tolerance in a human fungal pathogen. Proceedings of the National Academy of Sciences of the USA 108, 14091-14096.

Figueiredo, A.C.; de Sanctis, D.; Gutiérrez-Gallego, R.; Cereija, T.B.; Macedo-Ribeiro, S.; Fuentes-Prior, P.; Pereira, P.J.B. (2012) Unique thrombin inhibition mechanism by anophelin, an anticoagulant from the malaria vector. Proceedings of the National Academy of Sciences of the USA 109, E3649-E3658

Thompson, R.E.; Liu, X.; Alonso-García, N.; Pereira, P.J.B.; Jolliffe, K.A.; Payne, R.J. (2014) Trifluoroethanethiol: An Additive for Efficient One-Pot Peptide Ligation-Desulfurization Chemistry. Journal of the American Chemical Society 136, 8161-8164.

Santos, J.A.; Alonso-García, N.; Macedo-Ribeiro, S.; Pereira, P.J.B. (2014) The unique regulation of Fe/S cluster biogenesis in a Gram-positive bacterium. Proceedings of the National Academy of Sciences of the USA 111, E2251-E2260.

 

Group Leader
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ppereira@ibmc.up.pt
People
PosDocs

Manso Garcia, Jose
jose.manso@i3s.up.pt

Ripoll Rozada , Jorge
jorge.rozada@ibmc.up.pt

Phd Students

Barros Reis Cereija, Tatiana
tatiana.cereija@ibmc.up.pt


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