Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
13 08 2020
13 08 2020
Historique:
pubmed:
2
7
2020
medline:
15
12
2020
entrez:
2
7
2020
Statut:
ppublish
Résumé
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 (
Identifiants
pubmed: 32605369
doi: 10.1021/acs.jmedchem.0c00770
pmc: PMC7429357
mid: NIHMS1610450
doi:
Substances chimiques
Enzyme Inhibitors
0
Methyltransferases
EC 2.1.1.-
NTMT1 protein, human
EC 2.1.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8419-8431Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM117275
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM127896
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI127793
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023168
Pays : United States
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