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An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains
Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, effo...
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| Published in: | Angewandte Chemie International Edition 2019-01, Vol.58 (4), p.1007-1012 |
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| creator | D'Ascenzio, Melissa Pugh, Kathryn M. Konietzny, Rebecca Berridge, Georgina Tallant, Cynthia Hashem, Shaima Monteiro, Octovia Thomas, Jason R. Schirle, Markus Knapp, Stefan Marsden, Brian Fedorov, Oleg Bountra, Chas Kessler, Benedikt M. Brennan, Paul E. |
| description | Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in‐gel visualization and pull‐down of the desired bromodomains.
Bromodomain‐containing proteins: Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops is reported. |
| doi_str_mv | 10.1002/anie.201807825 |
| format | article |
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Bromodomain‐containing proteins: Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops is reported.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.201807825</identifier><identifier>PMID: 30589164</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Acetylation ; activity-based protein profiling ; Amino Acid Sequence ; Amino acids ; Binding Sites ; bromodomain ; Cancer ; Carbamates - chemistry ; Catalysis ; chemical proteomics ; Communication ; Communications ; Conserved Sequence ; covalent probes ; Disruption ; Domains ; epigenetics ; Gene expression ; Gene regulation ; Histones - chemistry ; Lysine ; Lysine - chemistry ; Modulators ; Molecular Docking Simulation ; Protein Binding ; Protein Domains ; Proteins ; Pyridazines - chemistry ; Transcription factors ; Triazoles - chemistry ; Tyrosine</subject><ispartof>Angewandte Chemie International Edition, 2019-01, Vol.58 (4), p.1007-1012</ispartof><rights>2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.</rights><rights>2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5055-781e1a0870b0c46fc46e2a91b6e07f2e7680aa86c5906436fc287dce7d140bc73</citedby><cites>FETCH-LOGICAL-c5055-781e1a0870b0c46fc46e2a91b6e07f2e7680aa86c5906436fc287dce7d140bc73</cites><orcidid>0000-0002-8950-7646 ; 0000-0003-2449-6461</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30589164$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>D'Ascenzio, Melissa</creatorcontrib><creatorcontrib>Pugh, Kathryn M.</creatorcontrib><creatorcontrib>Konietzny, Rebecca</creatorcontrib><creatorcontrib>Berridge, Georgina</creatorcontrib><creatorcontrib>Tallant, Cynthia</creatorcontrib><creatorcontrib>Hashem, Shaima</creatorcontrib><creatorcontrib>Monteiro, Octovia</creatorcontrib><creatorcontrib>Thomas, Jason R.</creatorcontrib><creatorcontrib>Schirle, Markus</creatorcontrib><creatorcontrib>Knapp, Stefan</creatorcontrib><creatorcontrib>Marsden, Brian</creatorcontrib><creatorcontrib>Fedorov, Oleg</creatorcontrib><creatorcontrib>Bountra, Chas</creatorcontrib><creatorcontrib>Kessler, Benedikt M.</creatorcontrib><creatorcontrib>Brennan, Paul E.</creatorcontrib><title>An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains</title><title>Angewandte Chemie International Edition</title><addtitle>Angew Chem Int Ed Engl</addtitle><description>Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in‐gel visualization and pull‐down of the desired bromodomains.
Bromodomain‐containing proteins: Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops is reported.</description><subject>Acetylation</subject><subject>activity-based protein profiling</subject><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Binding Sites</subject><subject>bromodomain</subject><subject>Cancer</subject><subject>Carbamates - chemistry</subject><subject>Catalysis</subject><subject>chemical proteomics</subject><subject>Communication</subject><subject>Communications</subject><subject>Conserved Sequence</subject><subject>covalent probes</subject><subject>Disruption</subject><subject>Domains</subject><subject>epigenetics</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Histones - chemistry</subject><subject>Lysine</subject><subject>Lysine - chemistry</subject><subject>Modulators</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Protein Domains</subject><subject>Proteins</subject><subject>Pyridazines - chemistry</subject><subject>Transcription factors</subject><subject>Triazoles - chemistry</subject><subject>Tyrosine</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNqFkc9u1DAQxi0EoqVw5YgscemBXWwnjp0LUroqtFJVECpny3Fmd10ldrGzW-XGI_CMPAmz2rL8uXCwbOn7zTcz_gh5ydmcMybe2uBhLhjXTGkhH5FjLgWfFUoVj_FdFsVMacmPyLOcb5HXmlVPyVHBpK55VR6ToQm0caPf-nH68e37mc3Q0U8ptkBvbFrB6MOKXseA2sKOtp9G797QC79a9xNdxJAhbbGiGXyIaOQ7-hmy7zaQ6b0f1z7QsxSH2MXB-pCfkydL22d48XCfkC_vz28WF7Orjx8uF83VzEkmJY7MgVumFWuZK6slHhC25m0FTC0FqEoza3XlZM2qskBAaNU5UB0vWetUcULe7X3vNu0AqIQx2d7cJT_YNJlovflbCX5tVnFrqrIWvORocPpgkOJXXGY0g88O-t4GiJtsBK84tsYfRfT1P-ht3KSA6-0oxXghS4nUfE-5FHNOsDwMw5nZJWl2SZpDkljw6s8VDviv6BCo98C972H6j51pri_Pf5v_BP7OrT8</recordid><startdate>20190121</startdate><enddate>20190121</enddate><creator>D'Ascenzio, Melissa</creator><creator>Pugh, Kathryn M.</creator><creator>Konietzny, Rebecca</creator><creator>Berridge, Georgina</creator><creator>Tallant, Cynthia</creator><creator>Hashem, Shaima</creator><creator>Monteiro, Octovia</creator><creator>Thomas, Jason R.</creator><creator>Schirle, Markus</creator><creator>Knapp, Stefan</creator><creator>Marsden, Brian</creator><creator>Fedorov, Oleg</creator><creator>Bountra, Chas</creator><creator>Kessler, Benedikt M.</creator><creator>Brennan, Paul E.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8950-7646</orcidid><orcidid>https://orcid.org/0000-0003-2449-6461</orcidid></search><sort><creationdate>20190121</creationdate><title>An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains</title><author>D'Ascenzio, Melissa ; Pugh, Kathryn M. ; Konietzny, Rebecca ; Berridge, Georgina ; Tallant, Cynthia ; Hashem, Shaima ; Monteiro, Octovia ; Thomas, Jason R. ; Schirle, Markus ; Knapp, Stefan ; Marsden, Brian ; Fedorov, Oleg ; Bountra, Chas ; Kessler, Benedikt M. ; Brennan, Paul E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5055-781e1a0870b0c46fc46e2a91b6e07f2e7680aa86c5906436fc287dce7d140bc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acetylation</topic><topic>activity-based protein profiling</topic><topic>Amino Acid Sequence</topic><topic>Amino acids</topic><topic>Binding Sites</topic><topic>bromodomain</topic><topic>Cancer</topic><topic>Carbamates - chemistry</topic><topic>Catalysis</topic><topic>chemical proteomics</topic><topic>Communication</topic><topic>Communications</topic><topic>Conserved Sequence</topic><topic>covalent probes</topic><topic>Disruption</topic><topic>Domains</topic><topic>epigenetics</topic><topic>Gene expression</topic><topic>Gene regulation</topic><topic>Histones - chemistry</topic><topic>Lysine</topic><topic>Lysine - chemistry</topic><topic>Modulators</topic><topic>Molecular Docking Simulation</topic><topic>Protein Binding</topic><topic>Protein Domains</topic><topic>Proteins</topic><topic>Pyridazines - chemistry</topic><topic>Transcription factors</topic><topic>Triazoles - chemistry</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>D'Ascenzio, Melissa</creatorcontrib><creatorcontrib>Pugh, Kathryn M.</creatorcontrib><creatorcontrib>Konietzny, Rebecca</creatorcontrib><creatorcontrib>Berridge, Georgina</creatorcontrib><creatorcontrib>Tallant, Cynthia</creatorcontrib><creatorcontrib>Hashem, Shaima</creatorcontrib><creatorcontrib>Monteiro, Octovia</creatorcontrib><creatorcontrib>Thomas, Jason R.</creatorcontrib><creatorcontrib>Schirle, Markus</creatorcontrib><creatorcontrib>Knapp, Stefan</creatorcontrib><creatorcontrib>Marsden, Brian</creatorcontrib><creatorcontrib>Fedorov, Oleg</creatorcontrib><creatorcontrib>Bountra, Chas</creatorcontrib><creatorcontrib>Kessler, Benedikt M.</creatorcontrib><creatorcontrib>Brennan, Paul E.</creatorcontrib><collection>Open Access: Wiley-Blackwell Open Access Journals</collection><collection>Wiley-Blackwell Open Access Backfiles</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>D'Ascenzio, Melissa</au><au>Pugh, Kathryn M.</au><au>Konietzny, Rebecca</au><au>Berridge, Georgina</au><au>Tallant, Cynthia</au><au>Hashem, Shaima</au><au>Monteiro, Octovia</au><au>Thomas, Jason R.</au><au>Schirle, Markus</au><au>Knapp, Stefan</au><au>Marsden, Brian</au><au>Fedorov, Oleg</au><au>Bountra, Chas</au><au>Kessler, Benedikt M.</au><au>Brennan, Paul E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2019-01-21</date><risdate>2019</risdate><volume>58</volume><issue>4</issue><spage>1007</spage><epage>1012</epage><pages>1007-1012</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><abstract>Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in‐gel visualization and pull‐down of the desired bromodomains.
Bromodomain‐containing proteins: Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops is reported.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30589164</pmid><doi>10.1002/anie.201807825</doi><tpages>6</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0002-8950-7646</orcidid><orcidid>https://orcid.org/0000-0003-2449-6461</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation activity-based protein profiling Amino Acid Sequence Amino acids Binding Sites bromodomain Cancer Carbamates - chemistry Catalysis chemical proteomics Communication Communications Conserved Sequence covalent probes Disruption Domains epigenetics Gene expression Gene regulation Histones - chemistry Lysine Lysine - chemistry Modulators Molecular Docking Simulation Protein Binding Protein Domains Proteins Pyridazines - chemistry Transcription factors Triazoles - chemistry Tyrosine |
| title | An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains |
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