7K3D

The structure of NTMT1 in complex with compound DC1-13

Summary for 7K3D

• Entry DOI: 10.2210/pdb7k3d/pdb
• Descriptor: N-terminal Xaa-Pro-Lys N-methyltransferase 1, S-ADENOSYL-L-HOMOCYSTEINE, N~2~-{(2S)-1-[(naphthalen-1-yl)acetyl]-2,5-dihydro-1H-pyrrole-2-carbonyl}-L-lysyl-L-argininamide, ... (4 entities in total)
• Functional Keywords: methyltransferase, enzyme, inhibitor complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 56538.33

Authors

Chen, D.,Huang, R.,Noinaj, N. (deposition date: 2020-09-11, release date: 2021-04-14, Last modification date: 2023-10-18)

Primary citation

Chen, D.,Dong, G.,Deng, Y.,Noinaj, N.,Huang, R.
Structure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1.
Acs Med.Chem.Lett., 12:485-493, 2021

PubMed Abstract: Protein N-terminal methyltransferases (NTMTs) catalyze the methylation of the α-N-terminal amines of proteins starting with an X-P-K/R motif. NTMT1 has been implicated in various cancers and in aging, implying its role as a potential therapeutic target. Through structural modifications of a lead NTMT1 inhibitor, , we designed and synthesized a diverse set of inhibitors to probe the NTMT1 active site. The incorporation of a naphthyl group at the N-terminal region and an -aminobenzoic amide at the C-terminal region of generates the top cell-potent inhibitor , demonstrating increased activity on both purified NTMT1 (IC of 0.34 ± 0.02 μM) and the cellular α-N-terminal methylation level of regulator of chromosome condensation 1 (RCC1, IC value of 30 μM) in human colorectal cancer HT29 cells. Furthermore, exhibits over 300-fold selectivity to several methyltransferases. This study points out the direction for the development of more cell-potent inhibitors for NTMT1.

PubMed: 33738076
DOI: 10.1021/acsmedchemlett.1c00012

Experimental method

X-RAY DIFFRACTION (2.34 Å)