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PDBsum entry 1he5
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Biliverdin-ix beta reductase
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PDB id
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1he5
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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 human biliverdin ixbeta reductase, An early fetal bilirubin ixbeta producing enzyme.
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Authors
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P.J.Pereira,
S.Macedo-Ribeiro,
A.Párraga,
R.Pérez-Luque,
O.Cunningham,
K.Darcy,
T.J.Mantle,
M.Coll.
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Ref.
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Nat Struct Biol, 2001,
8,
215-220.
[DOI no: ]
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PubMed id
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Abstract
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Biliverdin IXbeta reductase (BVR-B) catalyzes the pyridine nucleotide-dependent
production of bilirubin-IXbeta, the major heme catabolite during early fetal
development. BVR-B displays a preference for biliverdin isomers without
propionates straddling the C10 position, in contrast to biliverdin IXalpha
reductase (BVR-A), the major form of BVR in adult human liver. In addition to
its tetrapyrrole clearance role in the fetus, BVR-B has flavin and ferric
reductase activities in the adult. We have solved the structure of human BVR-B
in complex with NADP+ at 1.15 A resolution. Human BVR-B is a monomer displaying
an alpha/beta dinucleotide binding fold. The structures of ternary complexes
with mesobiliverdin IValpha, biliverdin IXalpha, FMN and lumichrome show that
human BVR-B has a single substrate binding site, to which substrates and
inhibitors bind primarily through hydrophobic interactions, explaining its broad
specificity. The reducible atom of both biliverdin and flavin substrates lies
above the reactive C4 of the cofactor, an appropriate position for direct
hydride transfer. BVR-B discriminates against the biliverdin IXalpha isomer
through steric hindrance at the bilatriene side chain binding pockets. The
structure also explains the enzyme's preference for NADP(H) and its B-face
stereospecificity.
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Figure 2.
Figure 2. Human BVR-B binds specifically to NADP. a, Stereo
view of the NADP+ cofactor binding site. Putative hydrogen bonds
are shown as dotted green lines, and solvent molecules as red
spheres. The atom color code is the same as in Fig. 1b. The 1.15
Å 2F[o] - F[c] electron density map for the cofactor, contoured
at 1.5  ,
is shown in blue. Residues interacting with NADP+ are numbered.
b, Solid surface representation of human BVR-B in complex with
NADP+ showing the wide substrate binding site adjacent to the
cofactor. Electrostatic surface potentials are contoured from
-10 (red) to 10 (blue) k[B]T e^-1. The cofactor carbon atoms are
shown in white, phosphorous in yellow, nitrogens in blue and
oxygens in red.
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Figure 3.
Figure 3. Structural formulas of some human BVR-B substrates and
inhibitors. a, FMN is a BVR-B substrate, lumichrome an
inhibitor. b, Tetrapyrrole biliverdin IX  ,
mesobiliverdin IV and
12-ethyl-13-methyl-mesobiliverdin IV are
substrates; biliverdin IX is
an inhibitor. The formation of a bilirubin isomer results from
the reduction of C10 of the corresponding biliverdin (numbering
as indicated for biliverdin IX  ,
which is conserved for the bilatriene skeleton in all other
isomers). The ring nomenclature for all -isomers
is that shown for biliverdin IX .
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2001,
8,
215-220)
copyright 2001.
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