Laboratory for NMR Spectroscopy, Structural Research Centre, Research Centre for Natural Sciences, 2 Magyar Tudósok Körútja, H-1117 Budapest, Hungary.
Int J Mol Sci. 2022 Jan 3;23(1):505. doi: 10.3390/ijms23010505.
Disorders in bile acid transport and metabolism have been related to a number of metabolic disease states, atherosclerosis, type-II diabetes, and cancer. Bile acid-binding proteins (BABPs), a subfamily of intracellular lipid-binding proteins (iLBPs), have a key role in the cellular trafficking and metabolic targeting of bile salts. Within the family of iLBPs, BABPs exhibit unique binding properties including positive binding cooperativity and site-selectivity, which in different tissues and organisms appears to be tailored to the local bile salt pool. Structural and biophysical studies of the past two decades have shed light on the mechanism of bile salt binding at the atomic level, providing us with a mechanistic picture of ligand entry and release, and the communication between the binding sites. In this review, we discuss the emerging view of bile salt recognition in intestinal- and liver-BABPs, with examples from both mammalian and non-mammalian species. The structural and dynamic determinants of the BABP-bile-salt interaction reviewed herein set the basis for the design and development of drug candidates targeting the transcellular traffic of bile salts in enterocytes and hepatocytes.
胆汁酸转运和代谢的紊乱与多种代谢性疾病状态、动脉粥样硬化、2 型糖尿病和癌症有关。胆汁酸结合蛋白（BABP）是细胞内脂质结合蛋白（iLBPs）的一个亚家族，在胆汁盐的细胞内运输和代谢靶向中起关键作用。在 iLBPs 家族中，BABP 表现出独特的结合特性，包括正结合协同性和位点选择性，这在不同的组织和生物体中似乎是针对局部胆汁盐池量身定制的。过去二十年的结构和生物物理研究揭示了胆汁盐结合的原子水平机制，为我们提供了配体进入和释放以及结合位点之间通讯的机制图。在这篇综述中，我们讨论了肠道和肝脏 BABP 中胆汁盐识别的新观点，并提供了来自哺乳动物和非哺乳动物物种的例子。本文综述的 BABP-胆汁盐相互作用的结构和动态决定因素为设计和开发针对肠细胞和肝细胞中胆汁盐跨细胞转运的药物候选物奠定了基础。
