Structural analysis of proteins involved in various human diseases and research of new therapeutic strategies

Analysis of mutants of the human GCAP1 protein involved in cone dystrophy and retinal degeneration. GCAP1 is a calcium sensor that interacts with the GC protein by inhibiting or favoring the synthesis of cyclic GMP (cGMP) based on intracellular calcium concentration. The interaction between the two proteins changes in the presence of pathological mutations of GCAP1 that produce retinal degeneration. We are trying to better understand the molecular mechanisms of the alteration of GCAP1 to find small molecules that can compensate the effect of mutations by slowing down the degenerative process.

Analysis of small molecules that stabilize the interaction between the 2 human proteins VPS29 and VPS35. The complex between VPS29 and VPS35 is part of a larger protein complex called retromer that functions as a protein transporter within cells between the endosomes and the Golgi. Molecules that stabilize this complex can be useful in various human diseases including amyotrophic lateral sclerosis. After the production of the 2 recombinant proteins we are characterizing the complex and trying to obtain its 3D structure bound to some small molecules identified and optimized by in silico docking.

GATM (Glycine Amidinotransferase) is a human protein whose mutants provoke a rare genetic pathology that leads to kidney degeneration. Briefly, the mutations detected destabilize protein folding leading to the formation of amyloid fibrils. After the in silico characterization of the alterations induced by mutations (Reichold et al., J. Am. Soc. Nephrol, 2018) we are trying to analyse the crystallographic structure of some mutants.

TgpA is an essential protein for the bacterium Pseudomonas aeruginosa. This bacterium is dangerous especially in the context of hospital infections (multiresistant strains) and for complications induced in cystic fibrosis patients. Recently we have solved the 3D structure of TgpA as a first step for the identification of inhibitors to be developed as new antibiotics.

Members:
Michela Bollati
Federica Cossu
Matteo De Rosa
Eloise Mastrangelo
Mario Milani (Principal investigator)