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Insights into the bile acid transportation system: The human ileal lipid‐binding protein‐cholyltaurine complex and its comparison with homologous structures
Author(s) -
Kurz Michael,
Brachvogel Volker,
Matter Hans,
Stengelin Siegfried,
Thüring Harald,
Kramer Werner
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10289
Subject(s) - enterohepatic circulation , binding site , biochemistry , protein superfamily , chemistry , bile acid , protein structure , plasma protein binding , biology , gene
Bile acids are generated in vivo from cholesterol in the liver, and they undergo an enterohepatic circulation involving the small intestine, liver, and kidney. To understand the molecular mechanism of this transportation, it is essential to gain insight into the three‐dimensional (3D) structures of proteins involved in the bile acid recycling in free and complexed form and to compare them with homologous members of this protein family. Here we report the solution structure of the human ileal lipid‐binding protein (ILBP) in free form and in complex with cholyltaurine. Both structures are compared with a previously published structure of the porcine ILBP‐cholylglycine complex and with related lipid‐binding proteins. Protein structures were determined in solution by using two‐dimensional (2D)‐ and 3D‐homo and heteronuclear NMR techniques, leading to an almost complete resonance assignment and a significant number of distance constraints for distance geometry and restrained molecular dynamics simulations. The identification of several intermolecular distance constraints unambiguously determines the cholyltaurine‐binding site. The bile acid is deeply buried within ILBP with its flexible side‐chain situated close to the fatty acid portal as entry region into the inner ILBP core. This binding mode differs significantly from the orientation of cholylglycine in porcine ILBP. A detailed analysis using the GRID/CPCA strategy reveals differences in favorable interactions between protein‐binding sites and potential ligands. This characterization will allow for the rational design of potential inhibitors for this relevant system. Proteins 2003;50:312–328. © 2002 Wiley‐Liss, Inc.