7RCU

Synthetic Max homodimer mimic in complex with DNA

7RCU の概要

• エントリーDOI: 10.2210/pdb7rcu/pdb
• 分子名称: 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)
• 機能のキーワード: synthetic protein, complex, transcription factor mimic, dna binding protein, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 90424.62

構造登録者

Speltz, T.,Qiao, Z.,Shangguan, S.,Fanning, S.,Greene, J.,Moellering, R. (登録日: 2021-07-08, 公開日: 2022-09-14, 最終更新日: 2024-12-25)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (2.69 Å)