The Department of Biomedicine

BBB seminar: Pål Stenmark

Structural biology targeting human disease

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Pål Stenmark
Department of Biochemistry and Biophysics, Stockholm University, Sweden

Novel cancer targets in nucleotide metabolism

Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We study the specificity of MTH1 for its natural substrates and the binding of MTH1 to inhibitors, using X-ray crystallography. Structure-based drug design is vital to facilitate and direct the development of selective and potent inhibitors of MTH1. We validate MTH1 as an anticancer target in vivo and describe the small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells.

The botulinum neurotoxins

The botulinum neurotoxins (BoNTs) are a family of bacterial toxins. Despite being among the most toxic compounds known, BoNT/A and BoNT/B are extensively used therapeutically. The BoNTs generally achieve their high avidity and specificity for the neuron by binding two receptors. All serotypes bind gangliosides and different serotypes bind distinctive membrane protein receptors. We have solved the structure of a ternary complex of the binding domain of BoNT/B bound to the recognition domain of its protein receptor, Syt-II, as well as the ganglioside GD1a simultaneously, providing insight into the dual receptor binding of the BoNTs. We have also solved the structures of the complexes between BoNT/DC and human Syt-I and rat Syt-II. The structures revealed that BoNT/DC possesses a novel Syt binding site, distinct from the Syt binding site in BoNT/B. Our findings indicated that BoNT/DC could bind three receptors simultaneously, two ganglioside receptors and one protein receptor.

Chairperson: Petri Kursul, <petri.kursula@biomed.uib.no>, Department of Biomedicine