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Structural basis for specific inhibition of the deubiquitinase UCHL1

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  • Christian Grethe

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

  • Mirko Schmidt

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

  • Gian-Marvin Kipka

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

  • Rachel O’Dea

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

  • Kai Gallant

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

  • Petra Janning

    (Max Planck Institute of Molecular Physiology, Department of Chemical Biology)

  • Malte Gersch

    (Chemical Genomics Centre
    TU Dortmund University, Department of Chemistry and Chemical Biology)

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.

Suggested Citation

  • Christian Grethe & Mirko Schmidt & Gian-Marvin Kipka & Rachel O’Dea & Kai Gallant & Petra Janning & Malte Gersch, 2022. "Structural basis for specific inhibition of the deubiquitinase UCHL1," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33559-4
    DOI: 10.1038/s41467-022-33559-4
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    1. Yoko Goto & Lihua Zeng & Chan Joo Yeom & Yuxi Zhu & Akiyo Morinibu & Kazumi Shinomiya & Minoru Kobayashi & Kiichi Hirota & Satoshi Itasaka & Michio Yoshimura & Keiji Tanimoto & Masae Torii & Terumasa , 2015. "UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    2. Andrew P. Turnbull & Stephanos Ioannidis & Wojciech W. Krajewski & Adan Pinto-Fernandez & Claire Heride & Agnes C. L. Martin & Louise M. Tonkin & Elizabeth C. Townsend & Shane M. Buker & David R. Lanc, 2017. "Molecular basis of USP7 inhibition by selective small-molecule inhibitors," Nature, Nature, vol. 550(7677), pages 481-486, October.
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