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Structural characterisation of the regulation of the catalytic subunit of the COP9 signalosome: Identification of new opportunities for drug discovery

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posted on 2021-06-10, 10:40 authored by Kirsty Ford
CSN5 is an MPN+ domain protein which, when in complex with the COP9 signalosome (CSN) or its MPN- domain partner, CSN6, can deNEDDylate cullin-RING ligases (CRL) ceasing their activity (Kato & Yoneda‐Kato, 2009). CSN5 also has important non-catalytic activity. It is a prolific nuclear export protein, able to translocate p27 (Tomoda et al., 2002) as well as stabilising several proteins including c-Jun and the 9-1-1 DNA damage repair complex (Claret et al., 1996). Unsurprisingly, due to its interactions with several oncogenic and tumour suppressive proteins, CSN5 has been implicated in the initiation of several different cancer types (Adler et al., 2008, Lee et al., 2011, Pan et al., 2014, Shackleford et al., 2011).

There is still little understood about the mechanisms of activation of CSN5 by CSN6 due to low resolution structural data. Described here is a high resolution (1.9 Å) crystallographic system that was used to determine the intricate mechanisms of binding between CSN5 and CSN6. This system was also used to uncover a new functional pocket at the CSN5-CSN6 interface in which several compounds were fitted and tested for effect on activity using a developed fluorescence polarisation assay. Results from this assay have found several of these compounds to significantly increase CSN5 activity up to 4-fold. The discovery of this previously unknown pocket could provide a specific mechanism for targeting CSN5 as well as increasing our understanding of CSN5 structure and activity.

History

Supervisor(s)

Aude Echalier; Mark Carr

Date of award

2021-02-05

Author affiliation

Department of Molecular and Cell Biology

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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