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Identification of histone peptide binding specificity and small-molecule ligands for the TRIM33α and TRIM33β bromodomains
DOI:
10.1021/acschembio.2c00266
Authors:
Angelina R.
Sekirnik
(University of Oxford)
,
Jessica K.
Reynolds
(University of Oxford)
,
Larissa
See
(University of Oxford)
,
Joseph P.
Bluck
(University of Oxford)
,
Amy R.
Scorah
(University of Oxford)
,
Cynthia
Tallant
(Structural Genomics Consortium, University of Oxford, U.K.)
,
Bernadette
Lee
(University of Oxford)
,
Katarzyna B.
Leszczynska
(University of Oxford)
,
Rachel L.
Grimley
(Pfizer Ltd)
,
R. Ian
Storer
(Pfizer Ltd)
,
Marta
Malattia
(Evotec (UK) Ltd)
,
Sara
Crespillo
(Evotec (UK) Ltd)
,
Sofia
Caria
(Evotec (UK) Ltd)
,
Stephanie
Duclos
(Evotec (UK) Ltd)
,
Ester M.
Hammond
(University of Oxford)
,
Stefan
Knapp
(Structural Genomics Consortium, Goethe University)
,
Garrett M.
Morris
(University of Oxford)
,
Fernanda
Duarte
(University of Oxford)
,
Philip C.
Biggin
(University of Oxford)
,
Stuart J.
Conway
(University of Oxford)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Acs Chemical Biology
State:
Published (Approved)
Published:
September 2022
Abstract: TRIM33 is a member of the tripartite motif (TRIM) family of proteins, some of which possess E3 ligase activity and are involved in the ubiquitin-dependent degradation of proteins. Four of the TRIM family proteins, TRIM24 (TIF1α), TRIM28 (TIF1β), TRIM33 (TIF1γ) and TRIM66, contain C-terminal plant homeodomain (PHD) and bromodomain (BRD) modules, which bind to methylated lysine (KMen) and acetylated lysine (KAc), respectively. Here we investigate the differences between the two isoforms of TRIM33, TRIM33α and TRIM33β, using structural and biophysical approaches. We show that the N1039 residue, which is equivalent to N140 in BRD4(1) and which is conserved in most BRDs, has a different orientation in each isoform. In TRIM33β, this residue coordinates KAc, but this is not the case in TRIM33α. Despite these differences, both isoforms show similar affinities for H31–27K18Ac, and bind preferentially to H31–27K9Me3K18Ac. We used this information to develop an AlphaScreen assay, with which we have identified four new ligands for the TRIM33 PHD-BRD cassette. These findings provide fundamental new information regarding which histone marks are recognized by both isoforms of TRIM33 and suggest starting points for the development of chemical probes to investigate the cellular function of TRIM33.
Journal Keywords: Assays; Cancer; Genetics; Ligands; Peptides and proteins
Subject Areas:
Biology and Bio-materials,
Chemistry
Instruments:
I03-Macromolecular Crystallography
Added On:
03/10/2022 11:27
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Biophysics
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)