Steve Smerdon group

Structural biology of phosphorylation-dependent signalling in the cell-cycle and the response to DNA damage

The dynamic nature of signalling processes in cells requires them to be rapidly reversible, and this is generally achieved through protein phosphorylation by kinases. There are more than 500 distinct kinases encoded in the human genome and misregulation of phosphorylation is a primary cause of many cancers and other diseases. The response to DNA damage is mediated by a phosphorylation cascade that originates at the site of the lesion and is transduced to a variety of effector molecules and complexes. We are studying a group of proteins that may function as phosphorylation-dependent adaptors or scaffolding molecules in pathways that regulate the response to DNA damage.

Our studies have revealed the structures of 14-3-3, Forkhead-associated, Brca1-C-terminus and Polo-box domain complexes and have found a remarkable diversity in binding modes. These observations have led to an additional interest in the regulation of several kinases that play crucial roles in the DNA damage response and its integration into the cell cycle. By understanding the molecular basis of specificity within such an extensive web of regulatory interactions, we aim to determine why these processes run amok, and how drugs might be designed to combat the devastating effects associated with cancer and other diseases.

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The FHA-domain protein Rv1827 regulates three enzymes of the TCA cycle in Mycobacterium tuberculosis to control glutamate flux and nitrogen assimilation.

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The structure of Nijmegen-breakage syndrome protein 1 (Nbs1) shows how an unusual molecular architecture underpins its function through phosphorylation-dependent interactions. The green nuclear speckles show the locations of individual double-stranded DNA breaks that are under repair.

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Smerdon group

Dr Steve Smerdon

Steve Smerdon
ssmerdo@nimr.mrc.ac.uk

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