8CY2

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor APNEA (Compound 9)

8CY2 の概要

• エントリーDOI: 10.2210/pdb8cy2/pdb
• 分子名称: Site-specific DNA-methyltransferase (adenine-specific), DNA Strand 1, DNA Strand 2, ... (7 entities in total)
• 機能のキーワード: dna adenine methylation, protein-dna complex, transferase, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• 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: 234266.82

構造登録者

Horton, J.R.,Zhou, J.,Cheng, X. (登録日: 2022-05-22, 公開日: 2023-01-11, 最終更新日: 2023-10-25)

主引用文献

Zhou, J.,Horton, J.R.,Menna, M.,Fiorentino, F.,Ren, R.,Yu, D.,Hajian, T.,Vedadi, M.,Mazzoccanti, G.,Ciogli, A.,Weinhold, E.,Huben, M.,Blumenthal, R.M.,Zhang, X.,Mai, A.,Rotili, D.,Cheng, X.
Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile- Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.
J.Med.Chem., 66:934-950, 2023

PubMed Abstract: Antivirulence agents targeting endospore-transmitted infections are urgently needed. specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related -adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound (IC ∼ 0.4 μM and ∼ 0.2 μM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.

PubMed: 36581322
DOI: 10.1021/acs.jmedchem.2c01789

実験手法

X-RAY DIFFRACTION (2.81 Å)