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Science 306 (5693): 117-120

Copyright © 2004 by the American Association for the Advancement of Science

Ubistatins Inhibit Proteasome-Dependent Degradation by Binding the Ubiquitin Chain

Rati Verma,1 Noel R. Peters,2 Mariapina D'Onofrio,3 Gregory P. Tochtrop,2 Kathleen M. Sakamoto,1,4 Ranjani Varadan,3 Mingsheng Zhang,5 Philip Coffino,5 David Fushman,3 Raymond J. Deshaies,1 Randall W. King2*

Abstract: To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked cell cycle progression by inhibiting cyclin B proteolysis and inhibited degradation of ubiquitinated Sic1 by purified proteasomes. Ubistatins blocked the binding of ubiquitinated substrates to the proteasome by targeting the ubiquitin-ubiquitin interface of Lys48-linked chains. The same interface is recognized by ubiquitin-chain receptors of the proteasome, indicating that ubistatins act by disrupting a critical protein-protein interaction in the ubiquitin-proteasome system.

1 Department of Biology, Howard Hughes Medical Institute (HHMI), California Institute of Technology, Pasadena, CA 91125, USA.
2 Institute of Chemistry and Cell Biology and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
3 Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742, USA.
4 Division of Hematology-Oncology, Mattel Children's Hospital, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
5 Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143–0414, USA.

* To whom correspondence should be addressed. E-mail: randy_king{at}hms.harvard.edu

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