8FS2

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

Summary for 8FS2

• Entry DOI: 10.2210/pdb8fs2/pdb
• Descriptor: 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)
• Functional Keywords: dna adenine methylation, protein-dna complex, transferase, dna binding protein, transferase-dna-inhibitor complex, transferase/dna/inhibitor
• Biological source: Clostridioides difficile; More
• Total number of polymer chains: 9
• Total formula weight: 234499.65

Authors

Zhou, J.,Horton, J.R.,Cheng, X. (deposition date: 2023-01-09, release date: 2023-05-10, Last modification date: 2024-05-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.59 Å)