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Title: An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

Abstract

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF{sup Skp2} substrate p27{sup Kip1}. CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

Authors:
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  1. (Cellgene)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNNIHDOE - BASIC ENERGY SCIENCES
OSTI Identifier:
1019128
Resource Type:
Journal Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 145; Journal Issue: (7) ; 06, 2011; Journal ID: ISSN 0092-8674
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ENZYMES; LYSINE; NEOPLASMS; PROTEINS; RESIDUES; STABILITY; SUBSTRATES; TARGETS

Citation Formats

Ceccarelli, Derek F., Tang, Xiaojing, Pelletier, Benoit, Orlicky, Stephen, Xie, Weilin, Plantevin, Veronique, Neculai, Dante, Chou, Yang-Chieh, Ogunjimi, Abiodun, Al-Hakim, Abdallah, Varelas, Xaralabos, Koszela, Joanna, Wasney, Gregory A., Vedadi, Masoud, Dhe-Paganon, Sirano, Cox, Sarah, Xu, Shuichan, Lopez-Girona, Antonia, Mercurio, Frank, Wrana, Jeff, Durocher, Daniel, Meloche, Sylvain, Webb, David R., Tyers, Mike, Sicheri, Frank, Mount Sinai Hospital), Edinburgh), SG), and Montreal). An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme. United States: N. p., 2011. Web. doi:10.1016/j.cell.2011.05.039.
Ceccarelli, Derek F., Tang, Xiaojing, Pelletier, Benoit, Orlicky, Stephen, Xie, Weilin, Plantevin, Veronique, Neculai, Dante, Chou, Yang-Chieh, Ogunjimi, Abiodun, Al-Hakim, Abdallah, Varelas, Xaralabos, Koszela, Joanna, Wasney, Gregory A., Vedadi, Masoud, Dhe-Paganon, Sirano, Cox, Sarah, Xu, Shuichan, Lopez-Girona, Antonia, Mercurio, Frank, Wrana, Jeff, Durocher, Daniel, Meloche, Sylvain, Webb, David R., Tyers, Mike, Sicheri, Frank, Mount Sinai Hospital), Edinburgh), SG), & Montreal). An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme. United States. doi:10.1016/j.cell.2011.05.039.
Ceccarelli, Derek F., Tang, Xiaojing, Pelletier, Benoit, Orlicky, Stephen, Xie, Weilin, Plantevin, Veronique, Neculai, Dante, Chou, Yang-Chieh, Ogunjimi, Abiodun, Al-Hakim, Abdallah, Varelas, Xaralabos, Koszela, Joanna, Wasney, Gregory A., Vedadi, Masoud, Dhe-Paganon, Sirano, Cox, Sarah, Xu, Shuichan, Lopez-Girona, Antonia, Mercurio, Frank, Wrana, Jeff, Durocher, Daniel, Meloche, Sylvain, Webb, David R., Tyers, Mike, Sicheri, Frank, Mount Sinai Hospital), Edinburgh), SG), and Montreal). Tue . "An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme". United States. doi:10.1016/j.cell.2011.05.039.
@article{osti_1019128,
title = {An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme},
author = {Ceccarelli, Derek F. and Tang, Xiaojing and Pelletier, Benoit and Orlicky, Stephen and Xie, Weilin and Plantevin, Veronique and Neculai, Dante and Chou, Yang-Chieh and Ogunjimi, Abiodun and Al-Hakim, Abdallah and Varelas, Xaralabos and Koszela, Joanna and Wasney, Gregory A. and Vedadi, Masoud and Dhe-Paganon, Sirano and Cox, Sarah and Xu, Shuichan and Lopez-Girona, Antonia and Mercurio, Frank and Wrana, Jeff and Durocher, Daniel and Meloche, Sylvain and Webb, David R. and Tyers, Mike and Sicheri, Frank and Mount Sinai Hospital) and Edinburgh) and SG) and Montreal)},
abstractNote = {In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF{sup Skp2} substrate p27{sup Kip1}. CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.},
doi = {10.1016/j.cell.2011.05.039},
journal = {Cell},
issn = {0092-8674},
number = (7) ; 06, 2011,
volume = 145,
place = {United States},
year = {2011},
month = {9}
}