8fs1

CamA Adenine Methyltransferase Complexed to Cognate Substrate DNA and Inhibitor 11a (YD905)

spinqualitylabelsall models 8fs1, resolution 2.74Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fs1 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 2.74Å Ligands: EDO, K, YB0 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A031WG99_CLODI Publication Abstract from PubMed S-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 Clostridioides difficile-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 (6e and 7), we designed an adenosine analog (11a) 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 11a (IC(50) = 0.15 muM) is 10x and 5x more potent against CamA than 6e and 7, respectively. The structure of the CamA-DNA-inhibitor complex revealed that 11a 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. 11a 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 C. difficile infection. Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile-Specific DNA Adenine Methyltransferase.,Zhou J, Deng Y, Iyamu ID, Horton JR, Yu D, Hajian T, Vedadi M, Rotili D, Mai A, Blumenthal RM, Zhang X, Huang R, Cheng X ACS Chem Biol. 2023 Apr 21;18(4):734-745. doi: 10.1021/acschembio.3c00035. Epub , 2023 Feb 22. PMID:37082867 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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