title: The crystal structure of shikimate dehydrogenase (AroE) reveals a unique NADPH binding mode.
abstract: Shikimate dehydrogenase catalyzes the NADPH-dependent reversible reduction of 3-dehydroshikimate to shikimate. We report the first X-ray structure of shikimate dehydrogenase from Haemophilus influenzae to 2.4-A resolution and its complex with NADPH to 1.95-A resolution. The molecule contains two domains, a catalytic domain with a novel open twisted alpha/beta motif and an NADPH binding domain with a typical Rossmann fold. The enzyme contains a unique glycine-rich P-loop with a conserved sequence motif, GAGGXX, that results in NADPH adopting a nonstandard binding mode with the nicotinamide and ribose moieties disordered in the binary complex. A deep pocket with a narrow entrance between the two domains, containing strictly conserved residues primarily contributed by the catalytic domain, is identified as a potential 3-dehydroshikimate binding pocket. The flexibility of the nicotinamide mononucleotide portion of NADPH may be necessary for the substrate 3-dehydroshikimate to enter the pocket and for the release of the product shikimate.
authors.affiliation: Syrrx Inc., San Diego, California 92121, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.forename: Frank
authors.initials: F
authors.lastname: Von Delft
authors.forename: Alexei
authors.initials: A
authors.lastname: Brooun
authors.forename: Mark W
authors.initials: MW
authors.lastname: Knuth
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
authors.forename: Duncan E
authors.initials: DE
authors.lastname: McRee
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006193:Haemophilus influenzae / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D012765:Shikimic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C096387:3-dehydroshikimate; D012765:Shikimic Acid; D009249:NADP; D000429:Alcohol Oxidoreductases; C022641:Shikimate dehydrogenase