Structural and functional studies of human transporters: how small molecules cross the membrane
The team’s overall goal is to understand mechanisms of transport across cell membranes, necessary in all cells.
How the surrounding environment affects cellular functions is to date poorly understood, therefore it is fundamental to explore membrane-embedded protein transporters and channels and to develop models that enable targeting specific, individual molecular mechanisms. The function of transporters is key for normal metabolism of all mammalian cells, and plays critical roles in cellular balance and in a variety of enzymatic pathways. Deregulation of transport of small molecules has been associated with several human diseases. Using a multidisciplinary approach, including the powerful structural biology method of single particle cryo-electron microscopy (Cryo-EM), we will target the mechanisms of human transporters by determining structural differences between different transporters as well as structural details of their interactions. Despite its importance, the atomic-level mechanism of how some small molecules cross the membrane remains unknown. The initial phase of this project has been funded by a H2020 Marie Curie Individual Fellowship. Leveraging the investment made by the European Union, I have recently been awarded a Young Talent Grant by the Research Council of Norway that will fund this project for four years.
Over the past fifteen years, I have built my career working on challenging research projects, applying for and receiving my own funding whilst becoming well versed in protein biochemistry, biophysics, and structural biology. I received my doctorate from Johns Hopkins University in Biophysics where I pioneered the research in protein engineering and cellulases in the Barrick laboratory leading to synergistic enhancement of activity between cellulases and to the development of a high-throughput screen for testing cellulase activity (Cunha et al. 2013, Applied and Environmental Microbiology; Cunha et al. 2016, Proteins). I have also contributed, with Dr. Abrescia, to the understanding of the mechanism of structural tuning of the Hepatitis C virus cellular receptor CD81 large extracellular loop using x-ray crystallography (Cunha et al.2016, Structure)." Dr. Luecke and myself have established the first cryo-electron microscopy sample preparation and data processing pipeline for single particle analysis at UiO. With this setup, I have targeted Helicobacter pylori that chronically infects the human stomach and is a major cause for gastric cancer. The project is aimed at developing an innovative monotherapy to eradicate chronic infection by H. pylori. I have recently determined the structure of the 1.1 MDa Helicobacter pylori urease complex to 2.0 Å resolution with a novel inhibitor bound using single particle Cryo-EM (Cunha et al.* 2021, Nature Communications).
- 2021: Cunha E. S., Chen X., Gaitero M. S., Mills J. D., Luecke H. (2021) Cryo EM Structure of Helicobacter pylori inhibitor-bound urease at 2.0 Å resolution. Nature Communications 12: 230
- 2016: Cunha E.S., Sfriso P., Rojas A., Roversi P., Orozco M., Abrescia N. (2016) Structural and molecular dynamic studies of CD81LEL. Structure 25: 53-65.
- 2016: Cunha E.S., Hatem C.L., Barrick D. (2016) Synergistic enhancement of cellulase pairs linked by consensus ankyrin repeats: Determination of the roles of spacing, orientation, and enzyme identity. Proteins 84: 1043–54.
- 2013: Cunha E.S., Hatem C.L., Barrick D. (2013) Thermostability and cellulolytic activity effects of inserting cellulase catalytic domains into thermostable consensus ankyrin scaffolds. Applied Environmental Microbiology 79: 6684-96.
- 2011: Cunha E.S., Hatem C. L., and Barrick D. (2011) Natural and designed enzymes for cellulose degradation. In Advanced Biofuels and Bioproducts, Springer Publishing - Book Chapter.
- 2006: Magro F., Cunha E., Araújo F., Meireles E., Pereira P., Diniz-Ribeiro M., Veloso F., Medeiros R., Soares-da-Silva P. (2006) Dopamine D2 receptor polymorphisms in inflammatory bowel disease and the refractory response to treatment. Dig. Dis. Sci. 51: 2039-44.
- 2005: Fernandes P.A., ..., Cunha E., Ramos M. et al. (2005) New designs for inhibitors of the NFkB: DNA binding. Theor. Chem. Acc. 113: 197.
- 2004: Fernandes P.A., ..., Cunha E., Ramos, M., et al. (2004) Design of 2-cyclopentenone derivatives with enhanced NFkB:DNA binding inhibitory properties. J. Mol. Structure: Theochem. 685: 73-82.