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PDBsum entry 2vue
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Transport protein
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PDB id
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2vue
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References listed in PDB file
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Key reference
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Title
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Crystallographic analysis of human serum albumin complexed with 4z,15e-Bilirubin-Ixalpha.
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Authors
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P.A.Zunszain,
J.Ghuman,
A.F.Mcdonagh,
S.Curry.
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Ref.
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J Mol Biol, 2008,
381,
394-406.
[DOI no: ]
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PubMed id
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Abstract
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Bilirubin, an insoluble yellow-orange pigment derived from heme catabolism,
accumulates to toxic levels in individuals with impaired or immature liver
function. The resulting jaundice may be managed with phototherapy to isomerize
the biosynthetic 4Z,15Z-bilirubin-IXalpha to more soluble and excretable
isomers, such as 4Z,15E-bilirubin. Bilirubin and its configurational isomers are
transported to the liver by human serum albumin (HSA) but their precise binding
location(s) on the protein have yet to be determined. To investigate the
molecular details of their interaction, we co-crystallised bilirubin with HSA.
Strikingly, the crystal structure--determined to 2.42 A resolution--revealed the
4Z,15E-bilirubin-IXalpha isomer bound to an L-shaped pocket in sub-domain IB. We
also determined the co-crystal structure of HSA complexed with fusidic acid, an
antibiotic that competitively displaces bilirubin from the protein, and showed
that it binds to the same pocket. These results provide the first crystal
structure of a natural bilirubin pigment bound to serum albumin, challenge some
of the present conceptions about HSA-bilirubin interactions, and provide a sound
structural framework for finally resolving the long-standing question of where
4Z,15Z-bilirubin-IXalpha binds to the protein.
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Figure 1.
Fig. 1. Structure and stereochemistry of bilirubin and
fusidic acid. (a) Structures of 4Z,15Z-bilirubin-IXα and the
photoisomer, 4Z,15E-bilirubin-IXα, that is observed bound to
HSA in this study. Other possible configurational photoisomers
(4E,15Z-bilirubin and 4E,15E-bilirubin) are not shown. (b)
Structures of the M and P enantiomers of 4Z,15Z-bilirubin-IXα
in the “ridge-tile” conformation. (c) Structure of fusidic
acid.
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Figure 3.
Fig. 3. Crystal structure of HSA complexed with fusidic
acid. (a) Simulated annealing F[o] – F[c] omit map contoured
at 1.75σ showing the drug bound to sub-domain IB of HSA.
Fusidic acid is shown in a stick representation with atoms
colored by atom-type: C, light blue; O, red; N blue. (b) Overall
structure of HSA complexed with fusidic acid. The drug, depicted
with space-filling spheres, binds to sub-domains IB and IIIB.
(c) Detailed view of the interactions of fusidic acid with the
binding pocket in sub-domain IB. Hydrogen bonds are
indicated by broken yellow lines. Selected protein sidechains
are shown as sticks (with carbon atoms colored grey). (d) View
of the fit of fusidic acid to the binding pocket in sub-domain
IB (pink, semi-transparent surface). (e) Same as in d but
rotated  vert,
similar 90° about a vertical axis.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
381,
394-406)
copyright 2008.
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