PDBsum entry 6pvs

Transferase/transferase inhibitor

PDB id: 6pvs

Contents

Protein chains

270 a.a.

257 a.a.

Ligands

P0V ×4

Waters ×106

PDB id:

6pvs

Name:

Transferase/transferase inhibitor

Title:

Structure of nicotinamide n-methyltransferase (nnmt) in complex with inhibitor ll320

Structure:

Nnmt protein. Chain: a, b, c, d. Synonym: nicotinamide n-methyltransferase,isoform cra_a. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nnmt, hcg_39357. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.58Å R-factor: 0.237 R-free: 0.292

Authors:

N.Noinaj,R.Huang,D.Chen,R.Yadav

Key ref:

D.Chen et al. (2019). Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase. J Med Chem, 62, 10783-10797. PubMed id: 31724854 DOI: 10.1021/acs.jmedchem.9b01255

Date:

21-Jul-19 Release date: 27-Nov-19

Protein chains

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

Seq: 264 a.a.

Struc: 270 a.a.*

Protein chains

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

Seq: 264 a.a.

Struc: 257 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

DOI no: 10.1021/acs.jmedchem.9b01255

J Med Chem 62:10783-10797 (2019)

PubMed id: 31724854

Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase.

D.Chen, L.Li, K.Diaz, I.D.Iyamu, R.Yadav, N.Noinaj, R.Huang.

ABSTRACT

Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a K_i value of 1.6 ± 0.3 nM, which is the most potent inhibitor to date. The cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.