8VPH

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Containing Quinoline-based SGI-1027 Analog 455 and Inhibitor MC4741

This is a non-PDB format compatible entry.

Summary for 8VPH

• Entry DOI: 10.2210/pdb8vph/pdb
• Descriptor: Site-specific DNA-methyltransferase (adenine-specific), DNA Strand II, DNA Strand I, ... (6 entities in total)
• Functional Keywords: dna adenine methylation, protein-dna complex, transferase, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Clostridioides difficile; More
• Total number of polymer chains: 9
• Total formula weight: 233597.79

Authors

Zhou, J.,Horton, J.R.,Cheng, X. (deposition date: 2024-01-16, release date: 2024-09-25, Last modification date: 2024-10-02)

Primary citation

Zhou, J.,Chen, Q.,Ren, R.,Yang, J.,Liu, B.,Horton, J.R.,Chang, C.,Li, C.,Maksoud, L.,Yang, Y.,Rotili, D.,Zhang, X.,Blumenthal, R.M.,Chen, T.,Gao, Y.,Valente, S.,Mai, A.,Cheng, X.
Quinoline-based compounds can inhibit diverse enzymes that act on DNA.
Biorxiv, 2024

PubMed Abstract: DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine ( ) or methylpiperazine ( ) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) and CamA (which generates N6-methyladenine). Structurally, compounds and specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound elicits DNA damage response via p53 activation.

PubMed: 38617249
DOI: 10.1101/2024.04.03.587980

Experimental method

X-RAY DIFFRACTION (3.18 Å)