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Human ileal bile acid\u2010binding protein (hI\u2010BABP), a member of the family of intracellular lipid\u2010binding proteins (iLBPs), plays a key role in the transcellular trafficking and metabolic targeting of bile salts. Disorder\u2013order transitions and sparsely populated hidden states in hI\u2010BABP are thought to be key elements of ligand recognition, with implications for bile salt recycling and bile salt\u2010mediated signaling events. To improve our understanding of the structural determinants of hI\u2010BABP stability, high pressure NMR was used to probe local packing interactions and characterize the folding\/unfolding process. Heterogeneity in pressure response, revealed by residue\u2010specific analysis of chemical shift and intensity changes, indicates a deviation from two\u2010state unfolding. Four specific protein regions such as the N\u2010terminal \u03b2\u2010strand, the helical cap, a hydrophobic cluster at the bottom of the \u03b2\u2010barrel, and segments of the HIJ\u2010region have been found to exhibit a pressure response differing significantly from the rest of the protein. Our analysis further shows that a low\u2010populated higher\u2010energy state, inferred by NMR relaxation dispersion measurements, becomes less distinct from the ground state at high pressure, corroborating the hypothesis that conformational exchange between a closed and a more open EFGH\u2010region, which mediates ligand entry, is related to a partial unfolding of the protein. A pathway of destabilization induced by high hydrostatic pressure is proposed and discussed in relation to the response of iLBPs to other stress conditions.<\/jats:p>","DOI":"10.1002\/pro.70608","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:03:13Z","timestamp":1777892593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functionally related internal fluctuations in human ileal bile acid\u2010binding protein by high pressure nuclear magnetic resonance"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7747-9643","authenticated-orcid":false,"given":"Tamara","family":"Teski","sequence":"first","affiliation":[{"name":"Centre for Structural Science HUN\u2010REN Research Centre for Natural Sciences  Budapest Hungary"},{"name":"Doctoral School of Biology, Institute of Biology ELTE E\u00f6tv\u00f6s Lor\u00e1nd University  Budapest 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