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. Author manuscript; available in PMC: 2017 Nov 8.
Published in final edited form as: Nat Chem Biol. 2017 May 8;13(7):730–736. doi: 10.1038/nchembio.2376

Figure 5. Anhydrotetracycline binds to the active site of Tet(50), trapping FAD in the unproductive OUT conformation.

Figure 5

(a) Anhydrotetracycline binds the active site of Tet(50) and traps the FAD cofactor in the unproductive OUT conformation (orange) in monomer B. The IN conformation of FAD from monomer A is superimposed in grey for comparison, and sterically clashes with the D-ring hydroxyl of anhydrotetracycline. (b) Surface representation of Tet(50)+anhydrotetracycline reveals that the substrate-loading channel remains open, which corresponds to FAD locked in the OUT conformation. (c) In Tet(50)+anhydrotetracycline monomer B, FAD is OUT, the loop is open, and anhydrotetracycline is bound (not shown: in monomer A, FAD is IN, the loop is closed, no anhydrotetracycline is bound). (d) Residue Thr-207 in Tet(50) makes van der Waals interactions with the planar 6-methyl group of anhydrotetracycline (aTC) (yellow) in the bound orientation, but would sterically clash with the 6-methyl and 6-hydroxyl groups that branch from the C ring of tetracycline or chlortetracycline if bound in a flipped orientation.