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Characterization of two distinct modes of drug binding to human intestinal fatty acid binding protein.

Patil R, Laguerre A, Wielens J, Headey SJ, Williams ML, Hughes ML, Mohanty B, Porter CJ, Scanlon MJ
ACS Chem Biol 9 2526-34 (2014)
Cited: 13 times
EuropePMC logo PMID: 25144524

Abstract

The aqueous cytoplasm of cells poses a potentially significant barrier for many lipophilic drugs to reach their sites of action. Fatty acid binding proteins (FABPs) bind to poorly water-soluble fatty acids (FAs) and lipophilic compounds and facilitate their intracellular transport. Several structures of FA in complex with FABPs have been described, but data describing the binding sites of other lipophilic ligands including drugs are limited. Here the environmentally sensitive fluorophores, 1-anilinonapthalene 8-sulfonic acid (ANS), and 11-dansylamino undecanoic acid (DAUDA) were used to investigate drug binding to human intestinal FABP (hIFABP). Most drugs that bound hIFABP were able to displace both ANS and DAUDA. A notable exception was ketorolac, a non-steroidal anti-inflammatory drug that bound to hIFABP and displaced DAUDA but failed to displace ANS. Isothermal titration calorimetry revealed that for the majority of ligands including FA, ANS, and DAUDA, binding to hIFABP was exothermic. In contrast, ketorolac binding to hIFABP was endothermic and entropy-driven. The X-ray crystal structure of DAUDA-hIFABP revealed a FA-like binding mode where the carboxylate of DAUDA formed a network of hydrogen bonds with residues at the bottom of the binding cavity and the dansyl group interacted with residues in the portal region. In contrast, NMR chemical shift perturbation (CSP) data suggested that ANS bound only toward the bottom of the hIFABP cavity, whereas ketorolac occupied only the portal region. The CSP data further suggested that ANS and ketorolac were able to bind simultaneously to hIFABP, consistent with the lack of displacement of ANS observed by fluorescence and supported by a model of the ternary complex. The NMR solution structure of the ketorolac-hIFABP complex therefore describes a newly characterized, hydrophobic ligand binding site in the portal region of hIFABP.

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  1. Polarity-based fluorescence probes: properties and applications. Qin X, Yang X, Du L, Li M. RSC Med Chem 12 1826-1838 (2021)
  2. Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition. Yabut KCB, Isoherranen N. Drug Metab Dispos 51 700-717 (2023)
  3. The Multifunctional Family of Mammalian Fatty Acid-Binding Proteins. Storch J, Corsico B. Annu Rev Nutr 43 25-54 (2023)

Articles citing this publication (8)

  1. Fatty Acid-binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-activated Receptor α in a Ligand-selective Manner. Hughes ML, Liu B, Halls ML, Wagstaff KM, Patil R, Velkov T, Jans DA, Bunnett NW, Scanlon MJ, Porter CJ. J Biol Chem 290 13895-13906 (2015)
  2. Fatty acid binding proteins have the potential to channel dietary fatty acids into enterocyte nuclei. Esteves A, Knoll-Gellida A, Canclini L, Silvarrey MC, André M, Babin PJ. J Lipid Res 57 219-232 (2016)
  3. A ligand-induced structural change in fatty acid-binding protein 1 is associated with potentiation of peroxisome proliferator-activated receptor α agonists. Patil R, Mohanty B, Liu B, Chandrashekaran IR, Headey SJ, Williams ML, Clements CS, Ilyichova O, Doak BC, Genissel P, Weaver RJ, Vuillard L, Halls ML, Porter CJH, Scanlon MJ. J Biol Chem 294 3720-3734 (2019)
  4. Structural basis for the ligand-binding specificity of fatty acid-binding proteins (pFABP4 and pFABP5) in gentoo penguin. Lee CW, Kim JE, Do H, Kim RO, Lee SG, Park HH, Chang JH, Yim JH, Park H, Kim IC, Lee JH. Biochem Biophys Res Commun 465 12-18 (2015)
  5. Introducing the CSP Analyzer: A novel Machine Learning-based application for automated analysis of two-dimensional NMR spectra in NMR fragment-based screening. Fino R, Byrne R, Softley CA, Sattler M, Schneider G, Popowicz GM. Comput Struct Biotechnol J 18 603-611 (2020)
  6. Cryo-EM, X-ray diffraction, and atomistic simulations reveal determinants for the formation of a supramolecular myelin-like proteolipid lattice. Ruskamo S, Krokengen OC, Kowal J, Nieminen T, Lehtimäki M, Raasakka A, Dandey VP, Vattulainen I, Stahlberg H, Kursula P. J Biol Chem 295 8692-8705 (2020)
  7. Fatty Acid Binding Proteins Expressed at the Human Blood-Brain Barrier Bind Drugs in an Isoform-Specific Manner. Lee GS, Kappler K, Porter CJ, Scanlon MJ, Nicolazzo JA. Pharm Res 32 3432-3446 (2015)
  8. Identification of a non-classical three-dimensional nuclear localization signal in the intestinal fatty acid binding protein. Suárez M, Canclini L, Esteves A. PLoS One 15 e0242312 (2020)


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