7rcu | pdb_00007rcu

Synthetic Max homodimer mimic in complex with DNA

spinqualitylabelsall models 7rcu, resolution 2.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7rcu is a 24 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.69Å Ligands: ACE, ACM, D5M, V7J Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MAX_HUMAN Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MYC or MAD which recognizes the core sequence 5'-CAC[GA]TG-3'. The MYC-MAX complex is a transcriptional activator, whereas the MAD-MAX complex is a repressor. May repress transcription via the recruitment of a chromatin remodeling complex containing H3 'Lys-9' histone methyltransferase activity. Publication Abstract from PubMed 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. Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains.,Speltz TE, Qiao Z, Swenson CS, Shangguan X, Coukos JS, Lee CW, Thomas DM, Santana J, Fanning SW, Greene GL, Moellering RE Nat Biotechnol. 2023 Apr;41(4):541-551. doi: 10.1038/s41587-022-01504-x. Epub , 2022 Oct 27. PMID:36302987 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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