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7RCU

Synthetic Max homodimer mimic in complex with DNA

Summary for 7RCU
Entry DOI10.2210/pdb7rcu/pdb
DescriptorProtein 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 Keywordssynthetic protein, complex, transcription factor mimic, dna binding protein, transcription
Biological sourceHomo sapiens (human)
More
Total number of polymer chains24
Total formula weight90424.62
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 citationSpeltz, 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: 36302987
DOI: 10.1038/s41587-022-01504-x
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.69 Å)
Structure validation

238582

数据于2025-07-09公开中

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