p53 is arguably one of the most studied proteins because mutations on p53 are present in 50% of human cancers. However, there are still large gaps in our structural understanding of p53 function. From the five p53 domains only the structures of DNA-binding and the tetramerization domains are known, besides complex between a few amino acids from the activation and regulatory domains with p53 binding proteins. Only until very recently, efforts have started to find drugs that might overcome the cancerous effects of mutations in p53.
To design effective pharmacological interventions using p53 as a target is important to understand in atomic detail how to circumvent p53 negative regulators, how to rescue p53 mutants and how to induce other family members, like p73, to replace the function of p53.
We have recently solved structures of p73 DNA-binding domain in complex with DNA that show how p73 binds to four different response elements. We demonstrate that p73 binds DNA in an identical manner to p53 opening the possibility that p73 could substitute for p53 activity.
Bacterial Mercury Transport
Bacteria have an interesting mechanism to resist mercury toxicity that, if understood, could be used towards environmental decontamination efforts. As a mercury ion reaches the bacterial periplasm, a periplasmic protein, MerP, traps Hg+2, passes it to the membrane transporter MerT that translocates the ion to the cytoplasm where the mercury reductase MerA reduces it to the more volatile and less toxic Hg0 form. During the transport process, mercury cannot be released to the cytoplasm because it would randomly react with free sulfur groups.
The molecular details of how mercury is transported from MerP to MerT and then from MerT to MerA are unknown. Our current hypothesis contemplates 5 mercury binding sites: one in MerP, two in MerT and two in MerA (one of which is the final active site where mercury is reduced). In this project, we aim to understand the molecular mechanism that allows bacteria to capture mercury in the environment and transport it inside the cell where it is reduced.