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Crystal structure of the ternary complex of 1,3,8-trihydroxynaphthalene reductase from Magnaporthe grisea with NADPH and an active-site inhibitor. 1996

A Andersson, and D Jordan, and G Schneider, and Y Lindqvist
Department of Molecular Biology, Swedish University of Agricultural Sciences, Uppsala Biomedical Center, Uppsala, Sweden.

BACKGROUND The enzyme 1,3,8-trihydroxynaphthalene reductase (THNR) catalyzes an essential reaction in the biosynthesis of melanin, a black pigment crucial for the pathogenesis of the rice blast fungus, Magnaporthe grisea. The enzyme is the biochemical target of several commercially important fungicides which are used to prevent blast disease in rice plants. We have determined the structure of the ternary complex of THNR with bound NADPH and a fungicide, tricyclazole. RESULTS Crystallographic analysis showed four identical subunits of THNR to form a tetramer with 222 symmetry. The enzyme subunit consists of a single domain comprising a seven-stranded beta sheet flanked by eight alpha helices; the subunit contains a dinucleotide-binding fold which binds the coenzyme, NADPH. Tricyclazole, an inhibitor of the enzyme, binds at the active site in the vicinity of the NADPH nicotinamide ring. The active site contains a Ser-Tyr-Lys triad which is proposed to participate in catalysis. Coenzyme specificity is partly conferred by the interaction of a single basic residue, Arg39, with the 2' phosphate group of NADPH. CONCLUSIONS The structural model reveals THNR to belong to the family of short chain dehydrogenases. Despite the diversity of the chemical reactions catalyzed by this family of enzymes, their tertiary structures are very similar. In particular THNR has many amino acid sequence identities, and thus most probably high structural similarities, to enzymes involved in fungal aflatoxin synthesis. The structure of THNR in complex with NADPH and tricyclazole provides new insights into the structural basis of inhibitor binding. This new information may aid in the design of new inhibitors for rice crop protection.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009249 NADP Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (NMN) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2',5'-bisphosphate. It serves as an electron carrier in a number of reactions, being alternately oxidized (NADP+) and reduced (NADPH). (Dorland, 27th ed) Coenzyme II,Nicotinamide-Adenine Dinucleotide Phosphate,Triphosphopyridine Nucleotide,NADPH,Dinucleotide Phosphate, Nicotinamide-Adenine,Nicotinamide Adenine Dinucleotide Phosphate,Nucleotide, Triphosphopyridine,Phosphate, Nicotinamide-Adenine Dinucleotide
D010088 Oxidoreductases The class of all enzymes catalyzing oxidoreduction reactions. The substrate that is oxidized is regarded as a hydrogen donor. The systematic name is based on donor:acceptor oxidoreductase. The recommended name will be dehydrogenase, wherever this is possible; as an alternative, reductase can be used. Oxidase is only used in cases where O2 is the acceptor. (Enzyme Nomenclature, 1992, p9) Dehydrogenases,Oxidases,Oxidoreductase,Reductases,Dehydrogenase,Oxidase,Reductase
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005656 Fungal Proteins Proteins found in any species of fungus. Fungal Gene Products,Fungal Gene Proteins,Fungal Peptides,Gene Products, Fungal,Yeast Proteins,Gene Proteins, Fungal,Peptides, Fungal,Proteins, Fungal
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000935 Antifungal Agents Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics

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