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. Author manuscript; available in PMC: 2016 Mar 17.
Published in final edited form as: Biochemistry. 2015 Mar 3;54(10):1943–1955. doi: 10.1021/bi5014358

Figure 2.

Figure 2

Inhibitor binding modes. Direct interactions are highlighted by yellow dashed lines. The color code used for the different inhibitors is depicted in the lower, right corner. Selected protein residues and the cofactor are shown as gray sticks. (A) SaFabI inhibition by PT400 (yellow). The PT400 hydroxyl interacts with the Tyr157 hydroxyl group and the 2’-OH of the nicotinamide ribose at distances of 2.54 ± 0.09 Å and 2.44 ± 0.07 Å, respectively. Furthermore, the 4-F substituent forms weak hydrogen bonds with one of the two Phe204 Cε hydrogens as well as with the Ala198 Cα hydrogen (distances of 3.31 ± 0.07 Å and 3.35 ± 0.04 Å, respectively; for more details regarding such interactions see also reference 39). (B) SaFabI inhibition by MUT37307 (orange). As PT400, MUT37307 is hydrogen bonded to the Tyr157 and nicotinamide ribose hydroxyl groups at distances of 2.51 ± 0.04 Å and 2.48 ± 0.04 Å, respectively. The distances of the Phe204 Cε and Ala198 Cα atoms to the 4-F substituent of MUT37307 are 3.13 ± 0.04 Å and 3.41 ± 0.02 Å, respectively. (C) SaFabI inhibition by PT404 (brown). The PT404 Aring hydroxyl group is hydrogen bonded to the Tyr157 hydroxyl group and the 2’-OH of the nicotinamide ribose at distances of 2.50 ± 0.05 Å and 2.57 ± 0.03 Å, respectively. The 4’-nitro group interacts with the amide nitrogen of Ala97 at a distance of 2.99 ± 0.10 Å. As for PT400 and MUT37307, the 4-F substituent contacts one of the two Phe204 Cε hydrogens as well as the Ala198 Cα hydrogen at distances of 3.20 ± 0.12 Å and 3.38 ± 0.05 Å, respectively. (D) SaFabI inhibition by PT449 (pink). The OH group of PT449 is bound to Tyr157 and the 2’-OH of the NADP+ nicotinamide ribose at distances of 2.59 ± 0.14 Å and 2.64 ± 0.10 Å, respectively. Furthermore, a linear halogen bond is formed between the Ala97 carbonyl oxygen and the 4’-Br group of PT449 at a distance of 3.16 ± 0.11 Å 39. (E) SaFabI inhibition by PT12 (blue). As for the other inhibitors, the central interaction is formed between the PT12 A-ring hydroxyl group and the Tyr157 hydroxyl group as well as with the 2’-OH of the nicotinamide ribose at distances of 2.60 ± 0.08 Å and 2.59 ± 0.09 Å, respectively. In addition, the 4’-nitro group contacts the amide nitrogen of Ala97 at a distance of 3.00 ± 0.12 Å.