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PDBsum entry 4mcd
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Transferase/transferase inhibitor
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PDB id
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4mcd
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References listed in PDB file
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Key reference
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Title
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Selective inhibitors of bacterial t-Rna-(N(1)g37) methyltransferase (trmd) that demonstrate novel ordering of the lid domain.
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Authors
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P.J.Hill,
A.Abibi,
R.Albert,
B.Andrews,
M.M.Gagnon,
N.Gao,
T.Grebe,
L.I.Hajec,
J.Huang,
S.Livchak,
S.D.Lahiri,
D.C.Mckinney,
J.Thresher,
H.Wang,
N.Olivier,
E.T.Buurman.
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Ref.
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J Med Chem, 2013,
56,
7278-7288.
[DOI no: ]
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PubMed id
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Abstract
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The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly
conserved in both Gram-positive and Gram-negative bacterial pathogens.
Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a
suitable target for the design of novel antibacterials. Screening of a
collection of compound fragments using Haemophilus influenzae TrmD identified
inhibitory, fused thieno-pyrimidones that were competitive with
S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by
X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor
of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no
activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9.
This is the first report of selective, nanomolar inhibitors of TrmD with
demonstrated ability to order the TrmD lid in the absence of tRNA.
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