8CXS

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor MTA

Summary for 8CXS

• Entry DOI: 10.2210/pdb8cxs/pdb
• Descriptor: Site-specific DNA-methyltransferase (adenine-specific), DNA Strand 2, DNA Strand 1, ... (7 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: 234107.62

Authors

Horton, J.R.,Zhou, J.,Cheng, X. (deposition date: 2022-05-22, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.49 Å)