An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

Derek F. Ceccarelli; Xiaojing Tang; Benoit Pelletier; Stephen Orlicky; Weilin Xie; Veronique Plantevin; Dante Neculai; Yang-Chieh Chou; Abiodun Ogunjimi; Abdallah Al-Hakim; Xaralabos Varelas; Joanna Koszela; Gregory A. Wasney; Masoud Vedadi; Sirano Dhe-Paganon; Sarah Cox; Shuichan Xu; Antonia Lopez-Girona; Frank Mercurio; Jeff Wrana; Daniel Durocher; Sylvain Meloche; David R. Webb; Mike Tyers; Frank Sicheri

doi:10.1016/j.cell.2011.05.039

An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

Derek F. Ceccarelli, Xiaojing Tang, Benoit Pelletier, Stephen Orlicky, Weilin Xie, Veronique Plantevin, Dante Neculai, Yang-Chieh Chou, Abiodun Ogunjimi, Abdallah Al-Hakim, Xaralabos Varelas, Joanna Koszela, Gregory A. Wasney, Masoud Vedadi, Sirano Dhe-Paganon, Sarah Cox, Shuichan Xu, Antonia Lopez-Girona, Frank Mercurio, Jeff WranaDaniel Durocher, Sylvain Meloche, David R. Webb^*, Mike Tyers, Frank Sicheri

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 SCFSkp2 substrate p27(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.

Original language	English
Pages (from-to)	1075-1087
Number of pages	13
Journal	Cell
Volume	145
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2011.05.039
Publication status	Published - 24 Jun 2011

Keywords / Materials (for Non-textual outputs)

ACTIVATION
P27(KIP1)
COMPLEX
CELL-DIVISION
E2
F-BOX PROTEINS
PROTEOLYSIS
LIGASE
PROTEASOME SYSTEM
SUBSTRATE

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Ceccarelli, D. F., Tang, X., Pelletier, B., Orlicky, S., Xie, W., Plantevin, V., Neculai, D., Chou, Y.-C., Ogunjimi, A., Al-Hakim, A., Varelas, X., Koszela, J., Wasney, G. A., Vedadi, M., Dhe-Paganon, S., Cox, S., Xu, S., Lopez-Girona, A., Mercurio, F., ... Sicheri, F. (2011). An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme. Cell, 145(7), 1075-1087. https://doi.org/10.1016/j.cell.2011.05.039

@article{b8edbee40b0d464b8d9f4d17e3ff0cc5,

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 SCFSkp2 substrate p27(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.",

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author = "Ceccarelli, {Derek F.} and Xiaojing Tang and Benoit Pelletier and Stephen Orlicky and Weilin Xie and Veronique Plantevin and Dante Neculai and Yang-Chieh Chou and Abiodun Ogunjimi and Abdallah Al-Hakim and Xaralabos Varelas and Joanna Koszela and Wasney, {Gregory A.} and Masoud Vedadi and Sirano Dhe-Paganon and Sarah Cox and Shuichan Xu and Antonia Lopez-Girona and Frank Mercurio and Jeff Wrana and Daniel Durocher and Sylvain Meloche and Webb, {David R.} and Mike Tyers and Frank Sicheri",

year = "2011",

month = jun,

day = "24",

doi = "10.1016/j.cell.2011.05.039",

language = "English",

volume = "145",

pages = "1075--1087",

journal = "Cell",

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Ceccarelli, DF, Tang, X, Pelletier, B, Orlicky, S, Xie, W, Plantevin, V, Neculai, D, Chou, Y-C, Ogunjimi, A, Al-Hakim, A, Varelas, X, Koszela, J, Wasney, GA, Vedadi, M, Dhe-Paganon, S, Cox, S, Xu, S, Lopez-Girona, A, Mercurio, F, Wrana, J, Durocher, D, Meloche, S, Webb, DR, Tyers, M & Sicheri, F 2011, 'An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme', Cell, vol. 145, no. 7, pp. 1075-1087. https://doi.org/10.1016/j.cell.2011.05.039

TY - JOUR

T1 - An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

AU - Ceccarelli, Derek F.

AU - Tang, Xiaojing

AU - Pelletier, Benoit

AU - Orlicky, Stephen

AU - Xie, Weilin

AU - Plantevin, Veronique

AU - Neculai, Dante

AU - Chou, Yang-Chieh

AU - Ogunjimi, Abiodun

AU - Al-Hakim, Abdallah

AU - Varelas, Xaralabos

AU - Koszela, Joanna

AU - Wasney, Gregory A.

AU - Vedadi, Masoud

AU - Dhe-Paganon, Sirano

AU - Cox, Sarah

AU - Xu, Shuichan

AU - Lopez-Girona, Antonia

AU - Mercurio, Frank

AU - Wrana, Jeff

AU - Durocher, Daniel

AU - Meloche, Sylvain

AU - Webb, David R.

AU - Tyers, Mike

AU - Sicheri, Frank

PY - 2011/6/24

Y1 - 2011/6/24

N2 - 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 SCFSkp2 substrate p27(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.

AB - 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 SCFSkp2 substrate p27(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.

KW - ACTIVATION

KW - P27(KIP1)

KW - COMPLEX

KW - CELL-DIVISION

KW - E2

KW - F-BOX PROTEINS

KW - PROTEOLYSIS

KW - LIGASE

KW - PROTEASOME SYSTEM

KW - SUBSTRATE

U2 - 10.1016/j.cell.2011.05.039

DO - 10.1016/j.cell.2011.05.039

M3 - Article

SN - 0092-8674

VL - 145

SP - 1075

EP - 1087

JO - Cell

JF - Cell

IS - 7

ER -

An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme

Abstract

Keywords / Materials (for Non-textual outputs)

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