Structural characterisation of MDM2 RING domain and its binding partners

Prof Danny Huang, Ubiquitin Signalling

Post-translational modification by ubiquitin (Ub) regulates many cellular processes. Deregulation of ubiquitination is often associated with disease, including cancer. A key interest of the Ubiquitin Signalling group is to understand the regulation and mechanistic function of the Ub pathway.


Ubiquitin ligases (E3s) catalyse the final step of Ub transfer from the E2~ubiquitin intermediate to the protein target. Recruiting the ubiquitin-charged E2 at a RING-binding domain, MDM2 is an E3 ligase that plays a crucial role in regulating cancer. MDM2 modulates the activity of p53 tumour suppressor protein by inhibiting its transcriptional activity and targeting it for protein degradation. Despite promoting apoptosis and cell cycle arrest, drugs that prevent MDM2 and p53 binding have proven to be highly toxic in the treatment of cancer.


Our recent work demonstrated that the inhibition of MDM2 ubiquitin ligase activity – without affecting the binding of MDM2 and p53 - stabilises p53 but can still limit p53 activity under unstressed condition (Nomura et al. Nature Structural & Molecular Biology 2017). This suggests that targeting the RING domain is a promising strategy in altering the p53-MDM2 axis for cancer therapy.
We have now identified molecules that could modulate the function of the RING domain. The successful PhD candidate will apply structural, biochemical and cell biology to characterise the binding mode and to elucidate the mechanism of inhibiting RING E3s in cancer.

For informal enquiries, please email Prof Danny Huang (d.huang@beatson.gla.ac.uk)

To apply, please complete a PhD Studentship Form (in right-hand menu opposite). Application deadline: 3rd January 2020

 

References:

Gabrielsen et al. (2017) A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants. Mol Cell 68: 456-70 e10

Nomura et al. (2017) Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. Nat Struct Mol Biol 24: 578-87

Buetow and Huang (2016) Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Bio 17: 626-42

Buetow et al. (2015) Activation of a primed RING E3-E2-ubiquitin complex by non-covalent ubiquitin Mol Cell 58: 297-310

Dou et al. (2013) Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat Struct Mol Biol 20: 982-6

Roxburgh et al. (2012) Small molecules that bind the Mdm2 RING stabilize and activate p53 Carcinogenesis 33: 791-798

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