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PDBsum entry 6pvb
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Transferase/transferase inhibitor
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PDB id
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6pvb
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References listed in PDB file
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Key reference
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Title
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Probing the plasticity in the active site of protein n-Terminal methyltransferase 1 using bisubstrate analogues.
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Authors
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D.Chen,
C.Dong,
G.Dong,
K.Srinivasan,
J.Min,
N.Noinaj,
R.Huang.
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Ref.
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J Med Chem, 2020,
63,
8419-8431.
[DOI no: ]
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PubMed id
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Abstract
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The bisubstrate analogue strategy is a promising approach to develop potent and
selective inhibitors for protein methyltransferases. Herein, the interactions of
a series of bisubstrate analogues with protein N-terminal methyltransferase 1
(NTMT1) were examined to probe the molecular properties of the active site of
NTMT1. Our results indicate that a 2-C to 4-C atom linker enables its respective
bisubstrate analogue to occupy both substrate- and cofactor-binding sites of
NTMT1, but the bisubstrate analogue with a 5-C atom linker only interacts with
the substrate-binding site and functions as a substrate. Furthermore, the 4-C
atom linker is the optimal and produces the most potent inhibitor
(Ki,app = 130 ± 40 pM) for NTMT1 to date, displaying more
than 3000-fold selectivity for other methyltransferases and even for its
homologue NTMT2. This study reveals the molecular basis for the plasticity of
the active site of NTMT1. Additionally, our study outlines general guidance on
the development of bisubstrate inhibitors for any methyltransferases.
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