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Ostertag, M.S. ; Hutwelker, W. ; Plettenburg, O. ; Sattler, M. ; Popowicz, G.M.

Structural insights into BET client recognition of endometrial and prostate cancer-associated SPOP mutants.

J. Mol. Biol. 431, 2213-2221 (2019)
Postprint Forschungsdaten DOI PMC
Open Access Green
BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy. (C) 2019 Elsevier Ltd. All rights reserved.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Spop ; Bet Protein ; Cancer ; Ubiquitination ; X-ray Crystallograpgy; Mutations; Stabilization; Resistance; Inhibitors
ISSN (print) / ISBN 0022-2836
e-ISSN 1089-8638
Zeitschrift Journal of Molecular Biology
Quellenangaben Band: 431, Heft: 11, Seiten: 2213-2221 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 24-28 Oval Rd, London Nw1 7dx, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Institute of Medicinal Chemistry (IMC)