1g0n
From Proteopedia
(New page: 200px<br /><applet load="1g0n" size="450" color="white" frame="true" align="right" spinBox="true" caption="1g0n, resolution 2.0Å" /> '''STRUCTURE OF TRIHYDRO...) |
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| - | [[Image:1g0n.jpg|left|200px]]<br /><applet load="1g0n" size=" | + | [[Image:1g0n.jpg|left|200px]]<br /><applet load="1g0n" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1g0n, resolution 2.0Å" /> | caption="1g0n, resolution 2.0Å" /> | ||
'''STRUCTURE OF TRIHYDROXYNAPHTHALENE REDUCTASE IN COMPLEX WITH NADPH AND 4,5,6,7-TETRACHLORO-PHTHALIDE'''<br /> | '''STRUCTURE OF TRIHYDROXYNAPHTHALENE REDUCTASE IN COMPLEX WITH NADPH AND 4,5,6,7-TETRACHLORO-PHTHALIDE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: Trihydroxynaphthalene reductase catalyzes two intermediate | + | BACKGROUND: Trihydroxynaphthalene reductase catalyzes two intermediate steps in the fungal melanin biosynthetic pathway. The enzyme, a typical short-chain dehydrogenase, is the biochemical target of three commercial fungicides. The fungicides bind preferentially to the NADPH form of the enzyme. RESULTS: Three X-ray structures of the Magnaporthe grisea enzyme complexed with NADPH and two commercial and one experimental fungicide were determined at 1.7 A (pyroquilon), 2.0 A (2,3-dihydro-4-nitro-1H-inden-1-one, 1), and 2.1 A (phthalide) resolutions. The chemically distinct inhibitors occupy similar space within the enzyme's active site. The three inhibitors share hydrogen bonds with the side chain hydroxyls of Ser-164 and Tyr-178 via a carbonyl oxygen (pyroquilon and 1) or via a carbonyl oxygen and a ring oxygen (phthalide). Active site residues occupy similar positions among the three structures. A buried water molecule that is hydrogen bonded to the NZ nitrogen of Lys-182 in each of the three structures likely serves to stabilize the cationic form of the residue for participation in catalysis. CONCLUSIONS: The pro S hydrogen of NADPH (which is transferred as a hydride to the enzyme's naphthol substrates) is directed toward the carbonyl carbon of the inhibitors that mimic an intermediate along the reaction coordinate. Modeling tetrahydroxynaphthalene and trihydroxynaphthalene in the active site shows steric and electrostatic repulsion between the extra hydroxyl oxygen of the former substrate and the sulfur atom of Met-283 (the C-terminal residue), which accounts, in part, for the 4-fold greater substrate specificity for trihydroxynaphthalene over tetrahydroxynaphthalene. |
==About this Structure== | ==About this Structure== | ||
| - | 1G0N is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Magnaporthe_grisea Magnaporthe grisea] with NDP and PHH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Tetrahydroxynaphthalene_reductase Tetrahydroxynaphthalene reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.252 1.1.1.252] Full crystallographic information is available from [http:// | + | 1G0N is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Magnaporthe_grisea Magnaporthe grisea] with <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=PHH:'>PHH</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Tetrahydroxynaphthalene_reductase Tetrahydroxynaphthalene reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.252 1.1.1.252] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G0N OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Tetrahydroxynaphthalene reductase]] | [[Category: Tetrahydroxynaphthalene reductase]] | ||
| - | [[Category: Basarab, G | + | [[Category: Basarab, G S.]] |
| - | [[Category: Gatenby, A | + | [[Category: Gatenby, A A.]] |
| - | [[Category: Jordan, D | + | [[Category: Jordan, D B.]] |
[[Category: Liao, D.]] | [[Category: Liao, D.]] | ||
[[Category: Valent, B.]] | [[Category: Valent, B.]] | ||
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[[Category: short chain dehydrogenase]] | [[Category: short chain dehydrogenase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:44:43 2008'' |
Revision as of 10:44, 21 February 2008
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STRUCTURE OF TRIHYDROXYNAPHTHALENE REDUCTASE IN COMPLEX WITH NADPH AND 4,5,6,7-TETRACHLORO-PHTHALIDE
Overview
BACKGROUND: Trihydroxynaphthalene reductase catalyzes two intermediate steps in the fungal melanin biosynthetic pathway. The enzyme, a typical short-chain dehydrogenase, is the biochemical target of three commercial fungicides. The fungicides bind preferentially to the NADPH form of the enzyme. RESULTS: Three X-ray structures of the Magnaporthe grisea enzyme complexed with NADPH and two commercial and one experimental fungicide were determined at 1.7 A (pyroquilon), 2.0 A (2,3-dihydro-4-nitro-1H-inden-1-one, 1), and 2.1 A (phthalide) resolutions. The chemically distinct inhibitors occupy similar space within the enzyme's active site. The three inhibitors share hydrogen bonds with the side chain hydroxyls of Ser-164 and Tyr-178 via a carbonyl oxygen (pyroquilon and 1) or via a carbonyl oxygen and a ring oxygen (phthalide). Active site residues occupy similar positions among the three structures. A buried water molecule that is hydrogen bonded to the NZ nitrogen of Lys-182 in each of the three structures likely serves to stabilize the cationic form of the residue for participation in catalysis. CONCLUSIONS: The pro S hydrogen of NADPH (which is transferred as a hydride to the enzyme's naphthol substrates) is directed toward the carbonyl carbon of the inhibitors that mimic an intermediate along the reaction coordinate. Modeling tetrahydroxynaphthalene and trihydroxynaphthalene in the active site shows steric and electrostatic repulsion between the extra hydroxyl oxygen of the former substrate and the sulfur atom of Met-283 (the C-terminal residue), which accounts, in part, for the 4-fold greater substrate specificity for trihydroxynaphthalene over tetrahydroxynaphthalene.
About this Structure
1G0N is a Single protein structure of sequence from Magnaporthe grisea with and as ligands. Active as Tetrahydroxynaphthalene reductase, with EC number 1.1.1.252 Full crystallographic information is available from OCA.
Reference
Structures of trihydroxynaphthalene reductase-fungicide complexes: implications for structure-based design and catalysis., Liao D, Basarab GS, Gatenby AA, Valent B, Jordan DB, Structure. 2001 Jan 10;9(1):19-27. PMID:11342131
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