PDBsum entry 2vue

Transport protein

PDB id: 2vue

Contents

Protein chain

565 a.a. *

Ligands

BLA ×2

Waters ×15

* Residue conservation analysis

PDB id:

2vue

Name:

Transport protein

Title:

Human serum albumin complexed with 4z,15e-bilirubin-ix-alpha

Structure:

Serum albumin. Chain: a, b. Synonym: human serum albumin. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922

Resolution:

2.42Å R-factor: 0.218 R-free: 0.273

Authors:

P.A.Zunszain,J.Ghuman,S.Curry

Key ref:

P.A.Zunszain et al. (2008). Crystallographic analysis of human serum albumin complexed with 4Z,15E-bilirubin-IXalpha. J Mol Biol, 381, 394-406. PubMed id: 18602119 DOI: 10.1016/j.jmb.2008.06.016

Date:

24-May-08 Release date: 17-Jun-08

Protein chains

P02768  (ALBU_HUMAN) -  Albumin from Homo sapiens

Seq: 609 a.a.

Struc: 565 a.a.

DOI no: 10.1016/j.jmb.2008.06.016

J Mol Biol 381:394-406 (2008)

PubMed id: 18602119

Crystallographic analysis of human serum albumin complexed with 4Z,15E-bilirubin-IXalpha.

P.A.Zunszain, J.Ghuman, A.F.McDonagh, S.Curry.

ABSTRACT

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 381, 394-406) copyright 2008.

Figures were selected by an automated process.