Proteomics

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Molecular basis of USP7 inhibition by selective small molecule inhibitors


ABSTRACT: Modification by ubiquitin controls the stability of most cellular proteins, and deregulation contributes to a variety of human diseases such as cancer. Deubiquitinases (DUBs) remove ubiquitin from proteins, and the inhibition of DUBs has been recognized as a therapeutic strategy to induce degradation of specific proteins, a concept extendable to ‘undruggable’ targets such as transcription factors. However, this potential has remained untapped; specific small molecule inhibitors for DUBs are scarce and insights into mechanisms of action are limited. Ubiquitin specific protease (USP) 7 stabilises the oncogenic E3 ligase MDM2 that destabilises the tumour suppressor p53 and inhibition of USP7 results in MDM2 degradation and p53 re-activation in a variety of cancers. We here present two small molecule inhibitors, FT671 and FT827, that inhibit USP7 with nanomolar affinity and display exquisite specificity towards USP7 in vitro and in cells. USP7-inhibitor co-crystal structures reveal that both compounds target the auto-inhibited apo-form of USP7 and bind in proximity to the misaligned catalytic triad in a dynamic hydrophobic pocket that serves as the binding site for the ubiquitin C-terminus. The unique auto-inhibited conformation of apo USP7 differs from other USP DUBs, explaining compound selectivity. Consistent with USP7 target engagement in cells, FT671 destabilises MDM2, stabilises p53 and results in transcription of p53 target genes, induction of the tumour suppressor p21, and tumour growth inhibition in vivo.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Philip Charles  

LAB HEAD: Benedikt Kessler

PROVIDER: PXD006418 | Pride | 2018-04-05

REPOSITORIES: Pride

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Publications

Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Turnbull Andrew P AP   Ioannidis Stephanos S   Krajewski Wojciech W WW   Pinto-Fernandez Adan A   Heride Claire C   Martin Agnes C L ACL   Tonkin Louise M LM   Townsend Elizabeth C EC   Buker Shane M SM   Lancia David R DR   Caravella Justin A JA   Toms Angela V AV   Charlton Thomas M TM   Lahdenranta Johanna J   Wilker Erik E   Follows Bruce C BC   Evans Nicola J NJ   Stead Lucy L   Alli Cristina C   Zarayskiy Vladislav V VV   Talbot Adam C AC   Buckmelter Alexandre J AJ   Wang Minghua M   McKinnon Crystal L CL   Saab Fabienne F   McGouran Joanna F JF   Century Hannah H   Gersch Malte M   Pittman Marc S MS   Marshall C Gary CG   Raynham Tony M TM   Simcox Mary M   Stewart Lorna M D LMD   McLoughlin Sheila B SB   Escobedo Jaime A JA   Bair Kenneth W KW   Dinsmore Christopher J CJ   Hammonds Tim R TR   Kim Sunkyu S   Urbé Sylvie S   Clague Michael J MJ   Kessler Benedikt M BM   Komander David D  

Nature 20171018 7677


Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in variou  ...[more]

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