Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 381, Issue 2, Pages 394-406Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.06.016
Keywords
human serum albumin; bilirubin; crystal structure; fusidic acid; ligand binding
Categories
Funding
- Medical Research Council
- Wellcome Trust [DK-26307]
- National Institutes of Health
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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-IX alpha 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 billrubin with HSA. Strikingly, the crystal structure-determined to 2.42 angstrom resolution-revealed the 4Z,15E-bilirubin-IX alpha 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-IX alpha binds to the protein. (c) 2008 Elsevier Ltd. All rights reserved.
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