Structures of Trihydroxynaphthalene Reductase-Fungicide Complexes

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Structures of Trihydroxynaphthalene Reductase-Fungicide Complexes Der-Ing Liao, Gregory S. Basarab, Anthony A. Gatenby, Barbara Valent, Douglas B. Jordan Structure Volume 9, Issue 1, Pages 19-27 (January 2001) DOI: 10.1016/S0969-2126(00)00548-7

Figure 1 The Fungal Melanin Biosynthetic Pathway 3HNR, 1,3,8-trihydroxynaphthalene reductase. 4HNR, 1,3,6,8-tetrahydroxynaphthalene reductase. SD, scytalone dehydratase Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 2 Fungicides that Target the Function of Trihydroxynaphthalene Reductase Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 3 Structural Features of the Enzyme-Fungicide Complexes (a) Overlays (stereoview) of the Cα traces of the four X-ray structures of 3HNR-NADPH–inhibitor complexes. Green, tricyclazole complex; yellow, 1 complex; magenta, phthalide complex; blue, pyroquilon complex. NADPH is in red. (b) Overlays of four inhibitors from their orientation in the active site of 3HNR. The positions of the inhibitors were obtained by aligning the Cα atoms of 3HNR of the four ternary complexes. The top and bottom views are orthogonal to one another. (c) Definition of the binding site volume in the 3HNR-NADPH–pyroquilon complex. The space-filled model of pyroquilon occupies 50% of the binding site bordered by the protein (netting) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 3 Structural Features of the Enzyme-Fungicide Complexes (a) Overlays (stereoview) of the Cα traces of the four X-ray structures of 3HNR-NADPH–inhibitor complexes. Green, tricyclazole complex; yellow, 1 complex; magenta, phthalide complex; blue, pyroquilon complex. NADPH is in red. (b) Overlays of four inhibitors from their orientation in the active site of 3HNR. The positions of the inhibitors were obtained by aligning the Cα atoms of 3HNR of the four ternary complexes. The top and bottom views are orthogonal to one another. (c) Definition of the binding site volume in the 3HNR-NADPH–pyroquilon complex. The space-filled model of pyroquilon occupies 50% of the binding site bordered by the protein (netting) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 3 Structural Features of the Enzyme-Fungicide Complexes (a) Overlays (stereoview) of the Cα traces of the four X-ray structures of 3HNR-NADPH–inhibitor complexes. Green, tricyclazole complex; yellow, 1 complex; magenta, phthalide complex; blue, pyroquilon complex. NADPH is in red. (b) Overlays of four inhibitors from their orientation in the active site of 3HNR. The positions of the inhibitors were obtained by aligning the Cα atoms of 3HNR of the four ternary complexes. The top and bottom views are orthogonal to one another. (c) Definition of the binding site volume in the 3HNR-NADPH–pyroquilon complex. The space-filled model of pyroquilon occupies 50% of the binding site bordered by the protein (netting) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 4 Interactions of Inhibitors with Active Site Residues (a) 1. (b) Phthalide. (c) Pyroquilon. (d) Tricyclazole. Hydrogen bonds are indicated by dashed lines with distances between nonhydrogen atoms in Å. Protein and NADPH atoms with asterisks are 3.2–3.9 Å from the non-hydrogen atoms of the inhibitors. Inhibitor atoms with asterisks are 3.2–3.7 Å from the non-hydrogen atoms of the protein and NADPH Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 5 Docking of Substrates into the Enzyme Active Site (a) Modeling of substrate tetrahydroxynaphthalene (4HN) onto the inhibitor pyroquilon. (b) Replacement of pyroquilon with tetrahydroxynaphthalene in the active site of 3HNR (stereoview). Van der Waals dot surfaces are indicated for the sulfur atom of Met-283 and the C6 oxygen of 4HN. (c) Replacement of pyroquilon with vermelone in the active site of 3HNR (stereoview) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 5 Docking of Substrates into the Enzyme Active Site (a) Modeling of substrate tetrahydroxynaphthalene (4HN) onto the inhibitor pyroquilon. (b) Replacement of pyroquilon with tetrahydroxynaphthalene in the active site of 3HNR (stereoview). Van der Waals dot surfaces are indicated for the sulfur atom of Met-283 and the C6 oxygen of 4HN. (c) Replacement of pyroquilon with vermelone in the active site of 3HNR (stereoview) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 5 Docking of Substrates into the Enzyme Active Site (a) Modeling of substrate tetrahydroxynaphthalene (4HN) onto the inhibitor pyroquilon. (b) Replacement of pyroquilon with tetrahydroxynaphthalene in the active site of 3HNR (stereoview). Van der Waals dot surfaces are indicated for the sulfur atom of Met-283 and the C6 oxygen of 4HN. (c) Replacement of pyroquilon with vermelone in the active site of 3HNR (stereoview) Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 6 Stereoview of the Interactions of the Active Site Water Molecule in the 3HNR-NADPH–Pyroquilon Complex Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)

Figure 7 Proposed Mechanism for the 3HNR-Catalyzed Reduction of 3HN to Vermelone R is the remaining portion of NADPH or NADP+, 2′-phospho-ADP Structure 2001 9, 19-27DOI: (10.1016/S0969-2126(00)00548-7)