Summary information and primary citation
- PDB-id
- 7rcu; SNAP-derived features in text and JSON formats;
DNAproDB
- Class
- transcription
- Method
- X-ray (2.69 Å)
- Summary
- Synthetic max homodimer mimic in complex with DNA
- Reference
- Speltz TE, Qiao Z, Swenson CS, Shangguan X, Coukos JS, Lee CW, Thomas DM, Santana J, Fanning SW, Greene GL, Moellering RE (2023): "Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains." Nat.Biotechnol., 41, 541-551. doi: 10.1038/s41587-022-01504-x.
- Abstract
- 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.
