Structural basis for specific inhibition of the deubiquitinase UCHL1

Christian Grethe, Mirko Schmidt, Gian-Marvin Kipka, Rachel O’Dea, Kai Gallant, Petra Janning and Malte Gersch ()
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Christian Grethe: Chemical Genomics Centre
Mirko Schmidt: Chemical Genomics Centre
Gian-Marvin Kipka: Chemical Genomics Centre
Rachel O’Dea: Chemical Genomics Centre
Kai Gallant: Chemical Genomics Centre
Petra Janning: Max Planck Institute of Molecular Physiology, Department of Chemical Biology
Malte Gersch: Chemical Genomics Centre

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Ubiquitination regulates protein homeostasis and is tightly controlled by deubiquitinases (DUBs). Loss of the DUB UCHL1 leads to neurodegeneration, and its dysregulation promotes cancer metastasis and invasiveness. Small molecule probes for UCHL1 and DUBs in general could help investigate their function, yet specific inhibitors and structural information are rare. Here we report the potent and non-toxic chemogenomic pair of activity-based probes GK13S and GK16S for UCHL1. Biochemical characterization of GK13S demonstrates its stereoselective inhibition of cellular UCHL1. The crystal structure of UCHL1 in complex with GK13S shows the enzyme locked in a hybrid conformation of apo and Ubiquitin-bound states, which underlies its UCHL1-specificity within the UCH DUB family. Phenocopying a reported inactivating mutation of UCHL1 in mice, GK13S, but not GK16S, leads to reduced levels of monoubiquitin in a human glioblastoma cell line. Collectively, we introduce a set of structurally characterized, chemogenomic probes suitable for the cellular investigation of UCHL1.

Date: 2022
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DOI: 10.1038/s41467-022-33559-4

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