A Single Hydroxyl Group Governs Ligand Site Selectivity in Human Ileal Bile Acid Binding Protein

The recognition between proteins and their native ligands is fundamental to biological function. In vivo, human ileal bile acid binding protein (I-BABP) encounters a range of bile salts that vary in the number and position of steroidal hydroxyl groups and the presence and type of side-chain conjugat...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2004-09, Vol.126 (35), p.11024-11029
Main Authors: Tochtrop, Gregory P, DeKoster, Gregory T, Covey, Douglas F, Cistola, David P
Format: Article
Language:English
Subjects:
Binding Sites
Biological and medical sciences
Escherichia coli - genetics
Escherichia coli - metabolism
Fundamental and applied biological sciences. Psychology
Humans
Hydroxysteroid Dehydrogenases - chemistry
Hydroxysteroid Dehydrogenases - genetics
Hydroxysteroid Dehydrogenases - metabolism
Ileum - chemistry
Ileum - metabolism
Interactions. Associations
Intermolecular phenomena
Ligands
Molecular biophysics
Nuclear Magnetic Resonance, Biomolecular
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Structure-Activity Relationship
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Summary:The recognition between proteins and their native ligands is fundamental to biological function. In vivo, human ileal bile acid binding protein (I-BABP) encounters a range of bile salts that vary in the number and position of steroidal hydroxyl groups and the presence and type of side-chain conjugation. Therefore, it is necessary to understand how chemical variability in the ligand affects the energetic and structural aspects of its recognition. Here we report studies of the binding site selectivity of I-BABP for glycocholic (GCA) and glycochenodeoxycholic (GCDA) acids using isotope-enriched bile salts along with two-dimensional heteronuclear NMR methods. When I-BABP is presented with either GCA or GCDA alone, the ligands bind to both sites. However, when presented with an equimolar mixture of the two bile salts, GCDA binds exclusively to site 1 and GCA to site 2. This remarkable selectivity is governed by the presence or absence of a single hydroxyl group at the C-12 position of the steroid tetracycle. The basis for this site selectivity appears to be energetic rather then steric.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja047589c