A bivalent lysine-acetylated small-molecule binding site in MYC
Gupta, D. G.; Truica, M. I.; Steffeck, A. W. T.; Parker, J. B.; Ryan, D. H.; Pan, H.; Yang, W.; Lu, X.; Unno, K.; Quan, S.; Elmashae, A. A.; Kerber, M. M.; Brookins, C. E.; Han, H.; Dufficy, F.; Shim, J. g.; Lambert, M.; Ziarek, J. J.; Chakravarti, D.; Schiltz, G.; Abdulkadir, S. A.
Show abstract
MYC is an important, yet challenging target in oncology as it lacks traditional "druggable" pockets. Here we show that two regions of the MYC protein, the basic-Helix-Loop-Helix (bHLH) domain, and an extended MYC Box II (eMBII) come together to form a bivalent, high-affinity small-molecule MYC inhibitor (MYCi) binding site. CRISPR-tiling mutagenesis identified mutations in the vicinity of emBII and in bHLH regions that together confer MYCi resistance. Importantly, acetylation of lysine K148 in eMBII which is essential for MYC oncogenicity in vivo increased the predicted order of this region and enhanced MYCi binding affinity. Furthermore, MYCi selectively modulated the expression of the same genes regulated by lysine-acetylated MYC in cancer cells. These studies provide a rationale for the selective targeting of acetylated, oncogenic MYC with small molecules.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Targeting the Protein-Protein Interaction Between the CDC37 Co-Chaperone and Client Kinases by an Allosteric RAF Dimer Breaker 96%
- Protein proximity networks and functional evaluation of the Casein Kinase 1 γ family reveals unique roles for CK1γ3 in WNT signaling 96%
- Development of an inhibitory TTC7B selective nanobody that blocks EFR3 recruitment of PI4KA 95%
Similar papers in this journal
- SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species 96%
- A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated Protein Kinase C regulation 96%
- Combinatorial CRISPR screen reveals FYN and KDM4 as targets for synergistic drug combination for treating triple negative breast cancer 96%
Similar papers in this journal
- Proteasome Regulation by Reversible Tyrosine Phosphorylation at the Membrane 95%
- Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers 95%
- Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.