Summary information and primary citation
- PDB-id
-
8cxx;
DSSR-derived features in text and
JSON formats
- Class
- DNA binding protein-DNA
- Method
- X-ray (2.34 Å)
- Summary
- Cama adenine methyltransferase complexed to cognate
substrate DNA and compound 6
- Reference
-
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
(2023): "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. doi: 10.1021/acs.jmedchem.2c01789.
- Abstract
- Antivirulence agents targeting endospore-transmitted
<i>Clostridioides difficile</i> infections are
urgently needed. <i>C. difficile-</i>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
<i>S</i>-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
