8FS2

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor 11b (YD907)

8FS2 の概要

• エントリーDOI: 10.2210/pdb8fs2/pdb
• 分子名称: Site-specific DNA-methyltransferase (adenine-specific), DNA (5'-D(*TP*TP*CP*AP*AP*AP*AP*AP*GP*TP*CP*CP*CP*A)-3'), 1,2-ETHANEDIOL, ... (7 entities in total)
• 機能のキーワード: dna adenine methylation, protein-dna complex, transferase, dna binding protein, transferase-dna-inhibitor complex, transferase/dna/inhibitor
• 由来する生物種: Clostridioides difficile; 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 234499.65

構造登録者

Zhou, J.,Horton, J.R.,Cheng, X. (登録日: 2023-01-09, 公開日: 2023-05-10, 最終更新日: 2024-05-22)

主引用文献

Zhou, J.,Deng, Y.,Iyamu, I.D.,Horton, J.R.,Yu, D.,Hajian, T.,Vedadi, M.,Rotili, D.,Mai, A.,Blumenthal, R.M.,Zhang, X.,Huang, R.,Cheng, X.
Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile- Specific DNA Adenine Methyltransferase.
Acs Chem.Biol., 18:734-745, 2023

PubMed Abstract: -Adenosyl-l-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host-pathogen interactions, one of which is -specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds ( and ), we designed an adenosine analog () carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-ethyl moiety at the sulfur atom off the ribose ring. Compound (IC = 0.15 μM) is 10× and 5× more potent against CamA than and , respectively. The structure of the CamA-DNA-inhibitor complex revealed that adopts a U-shaped conformation, with the two branches folded toward each other, and the aliphatic and aromatic rings at the two ends interacting with one another. occupies the entire hydrophobic surface (apparently unique to CamA) next to the adenosine binding site. Our work presents a hybrid knowledge-based and fragment-based approach to generating CamA inhibitors that would be chemical agents to examine the mechanism(s) of action and therapeutic potentials of CamA in infection.

PubMed: 37082867
DOI: 10.1021/acschembio.3c00035

実験手法

X-RAY DIFFRACTION (2.59 Å)