7RKK

Structure of Nicotinamide N-Methyltransferase (NNMT) in complex with II399 (C2 space group)

Summary for 7RKK

• Entry DOI: 10.2210/pdb7rkk/pdb
• Descriptor: NNMT protein, 3-[3-(acetyl{[(1R,2R,3S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl]methyl}amino)prop-1-yn-1-yl]benzamide (3 entities in total)
• Functional Keywords: methyltransferase, inhibitor, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63895.93

Authors

Yadav, R.,Noinaj, N.,Iyamu, I.D.,Huang, R. (deposition date: 2021-07-22, release date: 2022-07-20, Last modification date: 2023-10-18)

Primary citation

Iyamu, I.D.,Vilseck, J.Z.,Yadav, R.,Noinaj, N.,Huang, R.
Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase.
Angew.Chem.Int.Ed.Engl., 61:e202114813-e202114813, 2022

PubMed Abstract: Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate inhibitor II399, demonstrating a K of 5.9 nM in a biochemical assay and a cellular IC value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399's low nM binding affinity. Notably, II399 is 1 000-fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell-potent inhibitors for other SAM-dependent methyltransferases.

PubMed: 35134268
DOI: 10.1002/anie.202114813

Experimental method

X-RAY DIFFRACTION (2.76 Å)