7U1M

Crystal structure of NTMT1 in complex with compound YD206

Summary for 7U1M

• Entry DOI: 10.2210/pdb7u1m/pdb
• Descriptor: N-terminal Xaa-Pro-Lys N-methyltransferase 1, S-ADENOSYL-L-HOMOCYSTEINE, (1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl {2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl}carbamate (3 entities in total)
• Functional Keywords: methyltransferase, enzyme, inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 56187.94

Authors

Yadav, R.,Noinaj, N. (deposition date: 2022-02-21, release date: 2022-12-14, Last modification date: 2024-11-13)

Primary citation

Dong, G.,Deng, Y.,Yasgar, A.,Yadav, R.,Talley, D.,Zakharov, A.V.,Jain, S.,Rai, G.,Noinaj, N.,Simeonov, A.,Huang, R.
Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.
J.Med.Chem., 65:12334-12345, 2022

PubMed Abstract: Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC = 0.42 μM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC = 0.5 μM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations.

PubMed: 36074125
DOI: 10.1021/acs.jmedchem.2c01050

Experimental method

X-RAY DIFFRACTION (3.17 Å)