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PDBsum entry 7odc
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of mammalian ornithine decarboxylase at 1.6 a resolution: stereochemical implications of plp-Dependent amino acid decarboxylases.
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Authors
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A.D.Kern,
M.A.Oliveira,
P.Coffino,
M.L.Hackert.
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Ref.
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Structure, 1999,
7,
567-581.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Pyridoxal-5'-phosphate (PLP) dependent enzymes catalyze a broad
range of reactions, resulting in bond cleavage at C alpha, C beta, or C gamma
carbons of D and L amino acid substrates. Ornithine decarboxylase (ODC) is a
PLP-dependent enzyme that controls a critical step in the biosynthesis of
polyamines, small organic polycations whose controlled levels are essential for
proper growth. ODC inhibition has applications for the treatment of certain
cancers and parasitic ailments such as African sleeping sickness. RESULTS: The
structure of truncated mouse ODC (mODC') was determined by multiple isomorphous
replacement methods and refined to 1.6 A resolution. This is the first structure
of a Group IV decarboxylase. The monomer contains two domains: an alpha/beta
barrel that binds the cofactor, and a second domain consisting mostly of beta
structure. Only the dimer is catalytically active, as the active sites are
constructed of residues from both monomers. The interactions stabilizing the
dimer shed light on its regulation by antizyme. The overall structure and the
environment of the cofactor are compared with those of alanine racemase.
CONCLUSIONS: The analysis of the mODC' structure and its comparison with alanine
racemase, together with modeling studies of the external aldimine intermediate,
provide insight into the stereochemical characteristics of PLP-dependent
decarboxylation. The structure comparison reveals stereochemical differences
with other PLP-dependent enzymes and the bacterial ODC. These characteristics
may be exploited in the design of new inhibitors specific for eukaryotic and
bacterial ODCs, and provide the basis for a detailed understanding of the
mechanism by which these enzymes regulate reaction specificity.
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Figure 5.
Figure 5. Active site of mODC′ and comparison with ALR. (a)
Schematic drawing of the mODC′ active site illustrating the
hydrogen-bond interactions. Residues shown in bold face are
nearer the viewer. (b) Stereo figure of the active site of
mODC′ with electron density superimposed with its model. K69
of mODC′ is in Schiff-base linkage to the cofactor, E274 pairs
with the pyridine ring nitrogen N1, and H197 stacks on the si
face of the cofactor ring. Note the angle between K69 and the
pyridine ring of the cofactor exposing the si face. The map is a
2F[o]–F[c] map at 1.6 Å resolution contoured at 1.2σ.
(c) A view of the ALR and mODC′ active sites resulting from
the superposition of their cofactor rings. The mODC′ active
site is depicted in light gray. The figures were generated using
BOBSCRIPT [83], MOLSCRIPT [80] and Raster3D [81].
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1999,
7,
567-581)
copyright 1999.
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