3dap: Difference between revisions

Revision as of 20:09, 21 February 2008

C. GLUTAMICUM DAP DEHYDROGENASE IN COMPLEX WITH NADP+ AND THE INHIBITOR 5S-ISOXAZOLINE

OverviewOverview

The three-dimensional structures of Corynebacterium glutamicum diaminopimelate dehydrogenase as a binary complex with the substrate meso-diaminopimelate (meso-DAP) and a ternary complex with NADP+ and an isoxazoline inhibitor [Abbot, S.D., Lane-Bell, P., Kanwar, P.S.S., and Vederas, J. C. (1994) J. Am. Chem. Soc. 116, 6513-6520] have been solved and refined against X-ray diffraction data to 2.2 A. Diaminopimelate dehydrogenase is a homodimer of approximately 35,000 molecular weight subunits and is the only dehydrogenase present in the bacterial diaminopimelate/lysine biosynthetic pathway. Inhibitors of the enzymes of L-lysine biosynthesis have been proposed as potential antibiotics or herbicides, since mammals lack this metabolic pathway. Diaminopimelate dehydrogenase catalyzes the unique, reversible, pyridine dinucleotide-dependent oxidative deamination of the D-amino acid stereocenter of meso-diaminopimelate to generate L-2-amino-6-oxopimelate. The enzyme is absolutely specific for the meso stereoisomer of DAP and must distinguish between two opposite chiral amino acid centers on the same symmetric substrate. The determination of the three-dimensional structure of the enzyme--meso-diaminopimelate complex allows a description of the molecular basis of this stereospecific discrimination. The substrate is bound in an elongated cavity, in which the distribution of residues that act as hydrogen bond donors or acceptors defines a single orientation in which the substrate may bind in order to position the D-amino acid center of meso-DAP near the oxidized nucleotide. The previously described isoxazoline inhibitor binds at the same site as DAP but has its L-amino acid center positioned where the D-amino acid center of meso-DAP would normally be located, thereby generating a nonproductive inhibitor complex. The relative positions of the N-terminal dinucleotide and C-terminal substrate-binding domains in the diaminopimelate dehydrogenase--NADP+, diaminopimelate dehydrogenase--DAP, and diaminopimelate dehydrogenase--NADP(+)--inhibitor complexes confirm our previous observations that the enzyme undergoes significant conformational changes upon binding of both dinucleotide and substrate.

About this StructureAbout this Structure

3DAP is a Single protein structure of sequence from Corynebacterium glutamicum with and as ligands. Active as Diaminopimelate dehydrogenase, with EC number 1.4.1.16 Known structural/functional Sites: , and . Full crystallographic information is available from OCA.

ReferenceReference

Substrate and inhibitor binding sites in Corynebacterium glutamicum diaminopimelate dehydrogenase., Scapin G, Cirilli M, Reddy SG, Gao Y, Vederas JC, Blanchard JS, Biochemistry. 1998 Mar 10;37(10):3278-85. PMID:9521647

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 ==Overview==
-The three-dimensional structures of Corynebacterium glutamicum, diaminopimelate dehydrogenase as a binary complex with the substrate, meso-diaminopimelate (meso-DAP) and a ternary complex with NADP+ and an, isoxazoline inhibitor [Abbot, S.D., Lane-Bell, P., Kanwar, P.S.S., and, Vederas, J. C. (1994) J. Am. Chem. Soc. 116, 6513-6520] have been solved, and refined against X-ray diffraction data to 2.2 A. Diaminopimelate, dehydrogenase is a homodimer of approximately 35,000 molecular weight, subunits and is the only dehydrogenase present in the bacterial, diaminopimelate/lysine biosynthetic pathway. Inhibitors of the enzymes of, L-lysine biosynthesis have been proposed as potential antibiotics or, herbicides, since mammals lack this metabolic pathway. Diaminopimelate, dehydrogenase catalyzes the unique, reversible, pyridine, dinucleotide-dependent oxidative deamination of the D-amino acid, stereocenter of meso-diaminopimelate to generate L-2-amino-6-oxopimelate., The enzyme is absolutely specific for the meso stereoisomer of DAP and, must distinguish between two opposite chiral amino acid centers on the, same symmetric substrate. The determination of the three-dimensional, structure of the enzyme--meso-diaminopimelate complex allows a description, of the molecular basis of this stereospecific discrimination. The, substrate is bound in an elongated cavity, in which the distribution of, residues that act as hydrogen bond donors or acceptors defines a single, orientation in which the substrate may bind in order to position the, D-amino acid center of meso-DAP near the oxidized nucleotide. The, previously described isoxazoline inhibitor binds at the same site as DAP, but has its L-amino acid center positioned where the D-amino acid center, of meso-DAP would normally be located, thereby generating a nonproductive, inhibitor complex. The relative positions of the N-terminal dinucleotide, and C-terminal substrate-binding domains in the diaminopimelate, dehydrogenase--NADP+, diaminopimelate dehydrogenase--DAP, and, diaminopimelate dehydrogenase--NADP(+)--inhibitor complexes confirm our, previous observations that the enzyme undergoes significant conformational, changes upon binding of both dinucleotide and substrate.
+The three-dimensional structures of Corynebacterium glutamicum diaminopimelate dehydrogenase as a binary complex with the substrate meso-diaminopimelate (meso-DAP) and a ternary complex with NADP+ and an isoxazoline inhibitor [Abbot, S.D., Lane-Bell, P., Kanwar, P.S.S., and Vederas, J. C. (1994) J. Am. Chem. Soc. 116, 6513-6520] have been solved and refined against X-ray diffraction data to 2.2 A. Diaminopimelate dehydrogenase is a homodimer of approximately 35,000 molecular weight subunits and is the only dehydrogenase present in the bacterial diaminopimelate/lysine biosynthetic pathway. Inhibitors of the enzymes of L-lysine biosynthesis have been proposed as potential antibiotics or herbicides, since mammals lack this metabolic pathway. Diaminopimelate dehydrogenase catalyzes the unique, reversible, pyridine dinucleotide-dependent oxidative deamination of the D-amino acid stereocenter of meso-diaminopimelate to generate L-2-amino-6-oxopimelate. The enzyme is absolutely specific for the meso stereoisomer of DAP and must distinguish between two opposite chiral amino acid centers on the same symmetric substrate. The determination of the three-dimensional structure of the enzyme--meso-diaminopimelate complex allows a description of the molecular basis of this stereospecific discrimination. The substrate is bound in an elongated cavity, in which the distribution of residues that act as hydrogen bond donors or acceptors defines a single orientation in which the substrate may bind in order to position the D-amino acid center of meso-DAP near the oxidized nucleotide. The previously described isoxazoline inhibitor binds at the same site as DAP but has its L-amino acid center positioned where the D-amino acid center of meso-DAP would normally be located, thereby generating a nonproductive inhibitor complex. The relative positions of the N-terminal dinucleotide and C-terminal substrate-binding domains in the diaminopimelate dehydrogenase--NADP+, diaminopimelate dehydrogenase--DAP, and diaminopimelate dehydrogenase--NADP(+)--inhibitor complexes confirm our previous observations that the enzyme undergoes significant conformational changes upon binding of both dinucleotide and substrate.
 ==About this Structure==
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 [[Category: Diaminopimelate dehydrogenase]]
 [[Category: Single protein]]
-[[Category: Blanchard, J.S.]]
+[[Category: Blanchard, J S.]]
 [[Category: Cirilli, M.]]
 [[Category: Gao, Y.]]
-[[Category: Reddy, S.G.]]
+[[Category: Reddy, S G.]]
 [[Category: Scapin, G.]]
-[[Category: Vederas, J.C.]]
+[[Category: Vederas, J C.]]
 [[Category: DA3]]
 [[Category: NDP]]
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 [[Category: oxidoreductase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 10:51:48 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:09:06 2008''