Addition/Correction Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX
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Correction to Discovery of Bisubstrate Inhibitors of Nicotinamide N‑Methyltransferase (NNMT) Nicolas Babault, Abdellah Allali-Hassani, Fengling Li, Jie Fan, Alex Yue, Kevin Ju, Feng Liu,* Masoud Vedadi,* Jing Liu,* and Jian Jin* Journal of Medicinal Chemistry 2018, 61, 1541−1551. DOI: 10.1021/acs.jmedchem.7b01422
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S Supporting Information *
Page 1546. The second paragraph should be revised to the following: Co-crystal Structure of Compound 6 in Complex with hNNMT. To elucidate the interactions between hNNMT and compound 6 at an atomic level, we obtained an X-ray co-crystal structure of hNNMT in complex with 6 at 2.3 Å (PDB code 6CHH, Figure 6A,B and Supporting Information Table S2).
We identified an incorrect assignment for the stereochemistry of the α-amino group of compound 6 in the co-crystal structure (PDB code 6B1A). We have corrected the co-crystal structure with a new PDB code 6CHH. Here we provide the corrections to be made for the article. Page 1546. Figure 6 and legend should be revised according to the Figure 6 shown in this Addition/Correction.
Figure 6. X-ray crystal structures. (A) X-ray crystal structure of a binary complex of 6 (green) and hNNMT (cyan) (PDB code 6CHH). The surface of the protein is shown in gray. (B) Key interactions between 6 and hNNMT. H-bond interactions are shown in yellow dotted lines. Water molecules are illustrated as red balls. (C) Overlay of the crystal structure of the hNNMT (cyan)−6 (green) binary complex (PDB code 6CHH) with the crystal structure of hNNMT (not shown)−nicotinamide (magenta)−SAH (yellow) complex (PDB code 3ROD). (D) Overlay of the crystal structure of the hNNMT (cyan)−6 (green) binary complex (PDB code 6CHH) with the crystal structure of monkey NNMT (not shown)−1 (blue)−SAH (yellow) complex (PDB code 5XVQ).
© XXXX American Chemical Society
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DOI: 10.1021/acs.jmedchem.8b00849 J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
Addition/Correction
The crystal asymmetric unit contains four independent, conformationally similar NNMT molecules. Overlay of these molecules gives rmsd values ranging from 0.105 to 0.205 Å. Electron density of compound 6 is unambiguously defined in all of the NNMT molecules. We superimposed our hNNMT−6 structure with the published hNNMT−nicotinamide−SAH complex (Figure 6C).32 Consistent with our bisubstrate inhibitor design hypothesis and docking model study, compound 6 does occupy both cofactor and substrate binding sites. The cofactor mimicking moiety of compound 6 overlays nicely with SAH, and the ligand−protein interactions in this binding pocket are conserved. For example, the carboxylate oxygen atoms form H-bonds with four hydroxyl groups from the side chains of Tyr20, Tyr25, Tyr69, and Thr163. The α-amino group locates within the hydrogen bond distance of Gly63, Thr163, and a water molecule. In addition, the ribose hydroxyl groups interact with the side chains of Asp85 and Asn90 through H-bonds. Moreover, the adenine moiety is sandwiched between Tyr86 and Ala169, and the adenine N1 nitrogen forms a H-bond with the main chain amide nitrogen of Val143. Besides the conserved H-bond with Asp142, the adenine N6-amino group of compound 6 indirectly interacts with Ala169 through a water mediated H-bond. The 3-amido phenyl group of compound 6 nests nicely between Leu164 and Tyr204 at the nicotinamide-binding site. Three important H-bond interactions with Ser201 and Ser213 are conserved. Compared to nicotinamide, the 3-amido phenyl moiety projects a little bit deeper in the substrate-binding site. Therefore, the direct hydrogen bond between the amide nitrogen of nicotinamide and Asp197 is lost. Instead, watermolecule-mediated H-bonds are observed between the amide nitrogen of compound 6 and three residues (Ala168, Leu164, and Asp197). Since the N1-nitrogen of nicotinamide was removed on 6, the interaction between the nicotinamide N1-nitrogen and Tyr20 is lost. Page 1549. PDB code 6B1A in the Associated Content section should be revised to PDB code 6CHH in the following two instances (in the Supporting Information paragraph and Accessions Codes paragraph, respectively:
Overlay of the crystal structure of the hNNMT (PDB 6CHH). The structure of human NNMT in complex with 6 has been deposited under PDB ID 6CHH. Supporting Information. Figure S5 (page S7) and Table S2 (page S9) should be revised according to the figure and table presented in this Addition/Correction. The corrected Supporting Information file is available via the link in the Supporting Information paragraph below. Table S2. Crystallography Data and Refinement Statistics (PDB 6CHH) hNNMTtm/6 Data collection Space group Cell dimensions a, b, c (Å) α, β, γ (deg) Molecule per asymmetric unit Resolution (Å) Rsym I/σI Completeness (%) Redundancy Refinement Resolution (Å) No. unique reflections Rwork/ Rfree No. atoms/average B-factor [Å2] Protein Compound Other Water R.m.s deviations Bond lengths (Å) Bond angles (deg) Ramachandran plot Most favored (%) Additional allowed (%) Outliers (%) Protein Data Bank entry a
P1 46.44, 62.56, 107.98 91.76, 98.05, 111.83 4 57.84−2.30 (2.42−2.30)a 0.141 (0.583) 7.9 (3.6) 89.1 (91.6) 3.3 (3.3) 2.30 44070 (21941) 0.168/0.229 8358/27.2 7971/27.1 152/37.3 8/42.5 227/26.4 0.008 1.037 97.7 2.3 0 6CHH
The values in parentheses refer to statistics in the highest bin.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00849.
Figure S5. Overlay of the crystal structure of the hNNMT (cyan)−6 (green) binary complex (PDB code 6CHH) with the crystal structure of mouse NNMT (not shown)−1 (blue)−SAH (yellow) complex (PDB code 5XVK). B
DOI: 10.1021/acs.jmedchem.8b00849 J. Med. Chem. XXXX, XXX, XXX−XXX
