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PDBsum entry 2a8x
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Oxidoreductase
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PDB id
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2a8x
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References listed in PDB file
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Key reference
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Title
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Crystal structure and functional analysis of lipoamide dehydrogenase from mycobacterium tuberculosis.
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Authors
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K.R.Rajashankar,
R.Bryk,
R.Kniewel,
J.A.Buglino,
C.F.Nathan,
C.D.Lima.
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Ref.
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J Biol Chem, 2005,
280,
33977-33983.
[DOI no: ]
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PubMed id
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Abstract
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We report the 2.4 A crystal structure for lipoamide dehydrogenase encoded by
lpdC from Mycobacterium tuberculosis. Based on the Lpd structure and sequence
alignment between bacterial and eukaryotic Lpd sequences, we generated single
point mutations in Lpd and assayed the resulting proteins for their ability to
catalyze lipoamide reduction/oxidation alone and in complex with other proteins
that participate in pyruvate dehydrogenase and peroxidase activities. The
results suggest that amino acid residues conserved in mycobacterial species but
not conserved in eukaryotic Lpd family members modulate either or both
activities and include Arg-93, His-98, Lys-103, and His-386. In addition, Arg-93
and His-386 are involved in forming both "open" and "closed"
active site conformations, suggesting that these residues play a role in
dynamically regulating Lpd function. Taken together, these data suggest protein
surfaces that should be considered while developing strategies for inhibiting
this enzyme.
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Figure 1.
FIGURE 1. Structure of lipoamide dehydrogenase from M.
tuberculosis. A, ribbon representation of LPD dimer. Protomers
are colored blue or red. N and C demarcate the blue and red
polypeptide termini, respectively. Residues (Cys-41, Cys-46,
His-443', Glu-448') within the active sites are shown in stick
representation. FAD and the active site are indicated by arrows
and labeled. B, Stereo view and close-up of the active site with
respective active site residues in A labeled with putative
hydrogen bonds depicted as gray dashed lines. A simulated
annealing "omit" map is shown contoured around the FAD cofactor
at 1.0  . Structural
representations prepared with PyMol unless otherwise indicated
(34).
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Figure 4.
FIGURE 4. Cross-sectional view of the LPD active site in
two states. A, surface representation of Lpd illustrating both
open and closed conformation of the active site. B, individual
figures showing both open and closed states of the active site.
Arg-93, His-386, FAD, Cys-41 and Cys-46 are shown in stick
representation and labeled. Both MPD and FAD are indicated by
labels. The purported binding site for NADH and the lipoylated
DlaT side chain are indicated by arrows and labels in A.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
33977-33983)
copyright 2005.
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