Covalent-Fragment Screening of BRD4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites.

ACS Chemical Biology
M. D. OlpBrian C Smith

Abstract

BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to nonhomologous cysteine residues within the C-terminal BRD4 bromodomain (BRD4-BD2), we performed a midthroughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify BRD4. Subsequent mass spectrometry, NMR, and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to BRD4 among human bromodomains. This site is orthogonal to the BRD4-BD2 acetyl-lysine binding site as Cys356 modification ...Continue Reading

References

Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Jul 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·Y W JiangR D Kornberg
Jan 8, 1999·Journal of the American Society for Mass Spectrometry·Z Zhang, A G Marshall
May 1, 1964·Proceedings of the National Academy of Sciences of the United States of America·V G ALLFREYA E MIRSKY
Dec 7, 2006·The Journal of Biological Chemistry·Yoshihiro NakamuraShigeyuki Yokoyama
Mar 3, 2007·The Journal of Biological Chemistry·Shwu-Yuan Wu, Cheng-Ming Chiang
Aug 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Dwayne A BisgroveEric Verdin
Dec 24, 2008·Molecular and Cellular Biology·Bo HuangLin-Feng Chen
Jan 26, 2010·Nature Structural & Molecular Biology·Aaron J DonnerJoaquín M Espinosa
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 12, 2010·Nature·Edwige NicodemeAlexander Tarakhovsky
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 22, 2011·Expert Reviews in Molecular Medicine·Susanne MullerStefan Knapp
May 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Masafumi ToyoshimaCarla Grandori
May 31, 2012·The Journal of Biological Chemistry·Guangtao ZhangMing-Ming Zhou
Jun 23, 2012·Nature Reviews. Cancer·Anna C Belkina, Gerald V Denis
Aug 23, 2012·Proceedings of the National Academy of Sciences of the United States of America·Hozefa S BandukwalaAnjana Rao
Feb 20, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anna C BelkinaGerald V Denis
Mar 5, 2013·Journal of Biomolecular NMR·Jonathan J Helmus, Christopher P Jaroniec
Aug 14, 2013·Journal of Molecular and Cellular Cardiology·Jessica I SpiltoirTimothy A McKinsey
Oct 9, 2013·The Journal of Experimental Medicine·Deanna A MeleJose M Lora
Nov 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sarah PicaudPanagis Filippakopoulos
May 27, 2014·Nucleic Acids Research·Friederike ItzenMatthias Geyer
May 30, 2014·Journal of Medicinal Chemistry·Stefan G KathmanAlexander V Statsyuk
Jun 7, 2014·Molecular Cell·Junwei Shi, Christopher R Vakoc
Jun 12, 2014·Journal of Chemical Information and Modeling·Kai ZhuEdward Harder
Jul 24, 2014·Nature Reviews. Molecular Cell Biology·Chunaram ChoudharyMatthias Mann
Dec 17, 2014·Bioinformatics·Woonghee LeeJohn L Markley
Jan 1, 2015·Nature Reviews. Molecular Cell Biology·Eric Verdin, Melanie Ott

❮ Previous
Next ❯

Citations

Sep 3, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jorden A JohnsonWilliam C K Pomerantz
Oct 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Karishma PatelJoel P Mackay
Dec 5, 2020·Future Medicinal Chemistry·Elena De Vita
Feb 8, 2021·Current Opinion in Chemical Biology·Ronen Gabizon, Nir London
Aug 14, 2020·Cell Chemical Biology·Julie M Garlick, Anna K Mapp
May 14, 2021·The FEBS Journal·Marton Siklos, Stefan Kubicek
Aug 26, 2021·Biological Chemistry·Anna-Theresa BlaslMichael Lammers
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian WangXiaojun Yao

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.