Abstract
Gastrotropin, the intracellular carrier of bile salts in the small intestine, binds two ligand molecules simultaneously in its internal cavity. The molecular rearrangements required for ligand entry are not yet fully clear. To improve our understanding of the binding process we combined molecular dynamics simulations with previously published structural and dynamic NMR parameters. The resulting ensembles reveal two distinct modes of barrel opening with one corresponding to the transition between the apo and holo states, whereas the other affecting different protein regions in both ligation states. Comparison of the calculated structures with NMR-derived parameters reporting on slow conformational exchange processes suggests that the protein undergoes partial unfolding along a path related to the second mode of the identified barrel opening motion.
Highlights
Gastrotropin ( known as ileal bile acid-binding protein (I-BABP) or fatty acid-binding protein 6 (FABP6)) [1] is involved in the enterohepatic circulation of bile salts from the liver to the small intestine and back to the liver
Gastrotropin belongs to the family of intracellular lipid-binding proteins, a group of small, approximately 15-kDa proteins that bind fatty acids, retinoids, cholesterol, and bile salts [5]
Ligand binding in human gastrotropin exhibits positive cooperativity [9], which has been shown to be governed by the hydroxylation pattern of the bound bile salts [16]
Summary
Gastrotropin ( known as ileal bile acid-binding protein (I-BABP) or fatty acid-binding protein 6 (FABP6)) [1] is involved in the enterohepatic circulation of bile salts from the liver to the small intestine and back to the liver. Based on NMR structural and dynamic studies, a conformational selection mechanism of ligand binding involving an equilibrium between a closed and a more open protein state has been suggested for both the human ileal [14] and the chicken liver BABP analogues [23]. To improve our understanding of the mediatory role of internal motions in human gastrotropin-bile salt interaction, we generated conformational ensembles consistent with experimentally obtained NMR structural and dynamic data [25] and performed ligand docking to obtain an atomic-level insight into the binding mechanism. Our results reveal different conformational rearrangements in the protein that are suggested to correspond to motions characteristic of different time scales indicating a complex mechanism of bile salt entry
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