| Autor: |
Thomas E, Speltz, Zeyu, Qiao, Colin S, Swenson, Xianghang, Shangguan, John S, Coukos, Christopher W, Lee, Deborah M, Thomas, Jesse, Santana, Sean W, Fanning, Geoffrey L, Greene, Raymond E, Moellering |
| Rok vydání: |
2021 |
| Zdroj: |
Nature biotechnology. |
| ISSN: |
1546-1696 |
| Popis: |
Despite unequivocal roles in disease, transcription factors (TFs) remain largely untapped as pharmacologic targets due to the challenges in targeting protein-protein and protein-DNA interactions. Here we report a chemical strategy to generate modular synthetic transcriptional repressors (STRs) derived from the bHLH domain of MAX. Our synthetic approach yields chemically stabilized tertiary domain mimetics that cooperatively bind the MYC/MAX consensus E-box motif with nanomolar affinity, exhibit specificity that is equivalent to or beyond that of full-length TFs and directly compete with MYC/MAX protein for DNA binding. A lead STR directly inhibits MYC binding in cells, downregulates MYC-dependent expression programs at the proteome level and inhibits MYC-dependent cell proliferation. Co-crystallization and structure determination of a STR:E-box DNA complex confirms retention of DNA recognition in a near identical manner as full-length bHLH TFs. We additionally demonstrate structure-blind design of STRs derived from alternative bHLH-TFs, confirming that STRs can be used to develop highly specific mimetics of TFs targeting other gene regulatory elements. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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