7RCU
Synthetic Max homodimer mimic in complex with DNA
Summary for 7RCU
Entry DOI | 10.2210/pdb7rcu/pdb |
Descriptor | Protein max, DNA (5'-D(*A*GP*TP*AP*GP*CP*AP*CP*GP*TP*GP*CP*TP*AP*CP*TP*A)-3'), DNA (5'-D(*G*TP*AP*GP*CP*AP*CP*GP*TP*GP*CP*TP*AP*CP*TP*A)-3'), ... (8 entities in total) |
Functional Keywords | synthetic protein, complex, transcription factor mimic, dna binding protein, transcription |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 24 |
Total formula weight | 90424.62 |
Authors | Speltz, T.,Qiao, Z.,Shangguan, S.,Fanning, S.,Greene, J.,Moellering, R. (deposition date: 2021-07-08, release date: 2022-09-14, Last modification date: 2024-12-25) |
Primary citation | Speltz, T.E.,Qiao, Z.,Swenson, C.S.,Shangguan, X.,Coukos, J.S.,Lee, C.W.,Thomas, D.M.,Santana, J.,Fanning, S.W.,Greene, G.L.,Moellering, R.E. Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains. Nat.Biotechnol., 41:541-551, 2023 Cited by PubMed 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. PubMed: 36302987DOI: 10.1038/s41587-022-01504-x PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.69 Å) |
Structure validation
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