8cy2

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor APNEA (Compound 168)

spinqualitylabelsall models 8cy2, resolution 2.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8cy2 is a 9 chain structure with sequence from Clostridioides difficile. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.81Å Ligands: EDO, K, QA2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A031WG99_CLODI Publication Abstract from PubMed Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-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 S-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 39 (IC(50) approximately 0.4 muM and K(D) approximately 0.2 muM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors. Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.,Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, Huben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X J Med Chem. 2022 Dec 29. doi: 10.1021/acs.jmedchem.2c01789. PMID:36581322 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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