A single hydroxyl group governs ligand site selectivity in human ileal bile acid binding protein

Gregory P. Tochtrop, Gregory T. DeKoster, Douglas F. Covey, David P. Cistola

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)11024-11029
Number of pages6
JournalJournal of the American Chemical Society
Volume126
Issue number35
DOIs
StatePublished - Sep 8 2004

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