Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1
YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2019
|
| _version_ | 1797059399501479936 |
|---|---|
| author | Ni, X Heidenreich, D Christott, T Bennett, J Moustakim, M Brennan, P Fedorov, O Knapp, S Chaikuad, A |
| author_facet | Ni, X Heidenreich, D Christott, T Bennett, J Moustakim, M Brennan, P Fedorov, O Knapp, S Chaikuad, A |
| author_sort | Ni, X |
| collection | OXFORD |
| description | YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family. |
| first_indexed | 2024-03-06T20:03:41Z |
| format | Journal article |
| id | oxford-uuid:283530af-c64b-4638-9021-623f7aaeb0ff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:03:41Z |
| publishDate | 2019 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:283530af-c64b-4638-9021-623f7aaeb0ff2022-03-26T12:11:25ZStructural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:283530af-c64b-4638-9021-623f7aaeb0ffEnglishSymplectic Elements at OxfordAmerican Chemical Society2019Ni, XHeidenreich, DChristott, TBennett, JMoustakim, MBrennan, PFedorov, OKnapp, SChaikuad, AYEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family. |
| spellingShingle | Ni, X Heidenreich, D Christott, T Bennett, J Moustakim, M Brennan, P Fedorov, O Knapp, S Chaikuad, A Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title | Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title_full | Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title_fullStr | Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title_full_unstemmed | Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title_short | Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1 |
| title_sort | structural insights into interaction mechanisms of alternative piperazine urea yeats domain binders in mllt1 |
| work_keys_str_mv | AT nix structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT heidenreichd structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT christottt structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT bennettj structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT moustakimm structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT brennanp structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT fedorovo structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT knapps structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 AT chaikuada structuralinsightsintointeractionmechanismsofalternativepiperazineureayeatsdomainbindersinmllt1 |