PDBsum entry 6chh

Transferase/transferase inhibitor

PDB id: 6chh

Contents

Protein chains

269 a.a.

244 a.a.

Ligands

F0P ×4

EDO ×2

Waters ×226

PDB id:

6chh

Name:

Transferase/transferase inhibitor

Title:

Structure of human nnmt in complex with bisubstrate inhibitor ms2756

Structure:

Nicotinamide n-methyltransferase. Chain: a, b, c, d. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nnmt. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.171 R-free: 0.229

Authors:

N.Babault,J.Liu,J.Jin

Key ref:

N.Babault et al. (2018). Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem, 61, 1541-1551. PubMed id: 29320176

Date:

22-Feb-18 Release date: 13-Jun-18

Supersedes:

6b1a

Protein chains

P40261  (NNMT_HUMAN) -  Nicotinamide N-methyltransferase from Homo sapiens

Seq: 264 a.a.

Struc: 269 a.a.*

Protein chains

P40261  (NNMT_HUMAN) -  Nicotinamide N-methyltransferase from Homo sapiens

Seq: 264 a.a.

Struc: 244 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.2.1.1.1 - nicotinamide N-methyltransferase.
• Reaction: nicotinamide + S-adenosyl-L-methionine = 1-methylnicotinamide + S-adenosyl-L-homocysteine

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 61:1541-1551 (2018)

PubMed id: 29320176

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).

N.Babault, A.Allali-Hassani, F.Li, J.Fan, A.Yue, K.Ju, F.Liu, M.Vedadi, J.Liu, J.Jin.

ABSTRACT

Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-l-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays an important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6) and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.