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1.
ChemMedChem ; 13(15): 1555-1565, 2018 08 10.
Article in English | MEDLINE | ID: mdl-29862651

ABSTRACT

The p75 splice variant of lens epithelium-derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre-integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X-ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV-1 integrase core domain. Although the X-ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low-energy solution and bound conformations.


Subject(s)
HIV Integrase/chemistry , Intercellular Signaling Peptides and Proteins/chemistry , Molecular Mimicry , Peptides, Cyclic/chemistry , Crystallography, X-Ray , HIV-1/enzymology , Protein Conformation , Spectrum Analysis/methods
2.
J Biol Chem ; 291(18): 9411-24, 2016 Apr 29.
Article in English | MEDLINE | ID: mdl-26893375

ABSTRACT

Dynamin is a GTPase that mediates vesicle fission during synaptic vesicle endocytosis. Its long C-terminal proline-rich domain contains 13 PXXP motifs, which orchestrate its interactions with multiple proteins. The SH3 domains of syndapin and endophilin bind the PXXP motifs called Site 2 and 3 (Pro-786-Pro-793) at the N-terminal end of the proline-rich domain, whereas the amphiphysin SH3 binds Site 9 (Pro-833-Pro-836) toward the C-terminal end. In some proteins, SH3/peptide interactions also involve short distance elements, which are 5-15 amino acid extensions flanking the central PXXP motif for high affinity binding. Here we found two previously unrecognized elements in the central and the C-terminal end of the dynamin proline-rich domain that account for a significant increase in syndapin binding affinity compared with a previously reported Site 2 and Site 3 PXXP peptide alone. The first new element (Gly-807-Gly-811) is short distance element on the C-terminal side of Site 2 PXXP, which might contact a groove identified under the RT loop of the SH3 domain. The second element (Arg-838-Pro-844) is located about 50 amino acids downstream of Site 2. These two elements provide additional specificity to the syndapin SH3 domain outside of the well described polyproline-binding groove. Thus, the dynamin/syndapin interaction is mediated via a network of multiple contacts outside the core PXXP motif over a previously unrecognized extended region of the proline-rich domain. To our knowledge this is the first example among known SH3 interactions to involve spatially separated and extended long-range elements that combine to provide a higher affinity interaction.


Subject(s)
Carrier Proteins/chemistry , Dynamins/chemistry , Neuropeptides/chemistry , Phosphoproteins/chemistry , Adaptor Proteins, Signal Transducing , Amino Acid Motifs , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cytoskeletal Proteins , Dynamins/genetics , Dynamins/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Mice , Neuropeptides/genetics , Neuropeptides/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Binding , Rats , src Homology Domains
3.
ACS Chem Biol ; 9(11): 2526-34, 2014 Nov 21.
Article in English | MEDLINE | ID: mdl-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.


Subject(s)
Fatty Acid-Binding Proteins/metabolism , Fluorescent Dyes , Humans , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Spectrometry, Fluorescence
4.
Sci Rep ; 4: 4765, 2014 Apr 23.
Article in English | MEDLINE | ID: mdl-24755925

ABSTRACT

Hepatitis C virus (HCV) infection affects more than 170 million people. The high genetic variability of HCV and the rapid development of drug-resistant strains are driving the urgent search for new direct-acting antiviral agents. A new class of agents has recently been developed that are believed to target the HCV protein NS5A although precisely where they interact and how they affect function is unknown. Here we describe an in vitro assay based on microscale thermophoresis and demonstrate that two clinically relevant inhibitors bind tightly to NS5A domain 1 and inhibit RNA binding. Conversely, RNA binding inhibits compound binding. The compounds bind more weakly to known resistance mutants L31V and Y93H. The compounds do not affect NS5A dimerisation. We propose that current NS5A inhibitors act by favouring a dimeric structure of NS5A that does not bind RNA.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepacivirus/physiology , RNA, Viral/metabolism , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Drug Resistance, Viral/genetics , Genotype , Humans , In Vitro Techniques , Models, Molecular , Molecular Conformation , Molecular Docking Simulation , Mutation , Protein Binding/drug effects , Protein Interaction Domains and Motifs , Protein Multimerization/drug effects , Viral Nonstructural Proteins/chemistry
5.
Nat Rev Cancer ; 14(4): 248-62, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24622521

ABSTRACT

Historically, targeting protein-protein interactions with small molecules was not thought possible because the corresponding interfaces were considered mostly flat and featureless and therefore 'undruggable'. Instead, such interactions were targeted with larger molecules, such as peptides and antibodies. However, the past decade has seen encouraging breakthroughs through the refinement of existing techniques and the development of new ones, together with the identification and exploitation of unexpected aspects of protein-protein interaction surfaces. In this Review, we describe some of the latest techniques to discover modulators of protein-protein interactions and how current drug discovery approaches have been adapted to successfully target these interfaces.


Subject(s)
Neoplasms/drug therapy , Oncogene Proteins/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Neoplasms/metabolism , Oncogene Proteins/metabolism , Protein Binding , Protein Interaction Domains and Motifs , Protein Interaction Maps , Surface Properties
6.
J Biomol Screen ; 18(2): 147-59, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23139382

ABSTRACT

Fragment screening is becoming widely accepted as a technique to identify hit compounds for the development of novel lead compounds. In neighboring laboratories, we have recently, and independently, performed a fragment screening campaign on the HIV-1 integrase core domain (IN) using similar commercially purchased fragment libraries. The two campaigns used different screening methods for the preliminary identification of fragment hits; one used saturation transfer difference nuclear magnetic resonance spectroscopy (STD-NMR), and the other used surface plasmon resonance (SPR) spectroscopy. Both initial screens were followed by X-ray crystallography. Using the STD-NMR/X-ray approach, 15 IN/fragment complexes were identified, whereas the SPR/X-ray approach found 6 complexes. In this article, we compare the approaches that were taken by each group and the results obtained, and we look at what factors could potentially influence the final results. We find that despite using different approaches with little overlap of initial hits, both approaches identified binding sites on IN that provided a basis for fragment-based lead discovery and further lead development. Comparison of hits identified in the two studies highlights a key role for both the conditions under which fragment binding is measured and the criteria selected to classify hits.


Subject(s)
HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , Magnetic Resonance Spectroscopy/methods , Small Molecule Libraries , Surface Plasmon Resonance/methods , Crystallography, X-Ray , Drug Evaluation, Preclinical , HIV Integrase/chemistry , HIV Integrase/genetics , HIV Integrase Inhibitors/chemistry , Humans , Protein Binding/drug effects
7.
Proc Natl Acad Sci U S A ; 109(10): 3760-5, 2012 Mar 06.
Article in English | MEDLINE | ID: mdl-22355135

ABSTRACT

Syndapin I (PACSIN 1) is a synaptically enriched membrane tubulating protein that plays important roles in activity-dependent bulk endocytosis and neuronal morphogenesis. While syndapin I is an in vitro phosphoprotein, it is not known to be phosphorylated in neurons. Here, we report the identification of two phosphorylation sites, S76 and T181, of syndapin I from nerve terminals. Both residues are located at the N-terminal helix-capping motifs (N-Cap) of different α-helices in the F-BAR domain, important for F-BAR homodimer curvature and dimer-dimer filament assembly, respectively. Phospho-mimetic mutations of these residues regulate lipid-binding and tubulation both in vitro and in cells. Neither phosphosite regulated syndapin I function in activity-dependent bulk endocytosis. Rather, T181 phosphorylation was developmentally regulated and inhibited syndapin I function in neuronal morphogenesis. This suggests a novel mechanism for phosphorylation control of an F-BAR function through the regulation of α-helix interactions and stability within the folded F-BAR domain.


Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , Carrier Proteins/chemistry , Adaptor Proteins, Signal Transducing/physiology , Amino Acid Motifs , Animals , Brain/metabolism , Carrier Proteins/physiology , Cell Membrane/metabolism , Cytoskeletal Proteins , Endocytosis , Humans , Lipid Bilayers/chemistry , Lipids/chemistry , Models, Molecular , Molecular Conformation , Phosphoproteins/chemistry , Phosphorylation , Protein Structure, Tertiary , Rats , Synaptosomes/metabolism
8.
Article in English | MEDLINE | ID: mdl-21301109

ABSTRACT

Fatty-acid binding proteins (FABPs) are abundantly expressed proteins that bind a range of lipophilic molecules. They have been implicated in the import and intracellular distribution of their ligands and have been linked with metabolic and inflammatory responses in the cells in which they are expressed. Despite their high sequence identity, human intestinal FABP (hIFABP) and rat intestinal FABP (rIFABP) bind some ligands with different affinities. In order to address the structural basis of this differential binding, diffraction-quality crystals have been obtained of hIFABP and rIFABP in complex with the fluorescent fatty-acid analogue 11-(dansylamino)undecanoic acid.


Subject(s)
Fatty Acid-Binding Proteins/metabolism , Fatty Acids/metabolism , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , Crystallization , Crystallography, X-Ray/methods , Escherichia coli/genetics , Fatty Acid-Binding Proteins/analysis , Fatty Acid-Binding Proteins/genetics , Fatty Acid-Binding Proteins/isolation & purification , Humans , Hydrophobic and Hydrophilic Interactions , Intestinal Mucosa/metabolism , Ligands , Protein Binding/genetics , Rats , Sequence Homology, Amino Acid , Synchrotrons , Transformation, Bacterial , X-Ray Diffraction
10.
J Mol Recognit ; 24(2): 220-34, 2011.
Article in English | MEDLINE | ID: mdl-20540076

ABSTRACT

The diuretic drug ethacrynic acid (EA), both an inhibitor and substrate of pi class glutathione S-transferase (GST P1-1), has been tested in clinical trials as an adjuvant in chemotherapy. We recently studied the role of the active site residue Tyr-108 in binding EA to the enzyme and found that the analysis was complicated by covalent binding of this drug to the highly reactive Cys-47. Previous attempts to eliminate this binding by chemical modification yielded ambiguous results and therefore we decided here to produce a double mutant C47S/Y108V by site directed mutagenesis and further expression in Escherichia coli and the interaction of EA and its GSH conjugate (EASG) examined by calorimetric studies and X-ray diffraction. Surprisingly, in the absence of Cys-47, Cys-101 (located at the dimer interface) becomes a target for modification by EA, albeit at a lower conjugation rate than Cys-47. The Cys-47 → Ser mutation in the double mutant enzyme induces a positive cooperativity between the two subunits when ligands with affinity to G-site bind to enzyme. However, this mutation does not seem to affect the thermodynamic properties of ligand binding to the electrophilic binding site (H-site) and the thermal or chemical stability of this double mutant does not significantly affect the unfolding mechanism in either the absence or presence of ligand. Crystal structures of apo and an EASG complex are essentially identical with a few exceptions in the H-site and in the water network at the dimer interface.


Subject(s)
Cysteine/genetics , Diuretics/metabolism , Ethacrynic Acid/metabolism , Glutathione S-Transferase pi/chemistry , Glutathione S-Transferase pi/metabolism , Mutant Proteins/metabolism , Mutation/genetics , Amino Acid Substitution , Calorimetry , Crystallography, X-Ray , Enzyme Activation , Glutathione/metabolism , Humans , Hydrogen-Ion Concentration , Kinetics , Models, Molecular , Mutant Proteins/chemistry , Protein Multimerization , Structure-Activity Relationship , Substrate Specificity , Thermodynamics
11.
FEBS Lett ; 584(8): 1455-62, 2010 Apr 16.
Article in English | MEDLINE | ID: mdl-20227411

ABSTRACT

HIV integrase (IN) is an essential enzyme in HIV replication and an important target for drug design. IN has been shown to interact with a number of cellular and viral proteins during the integration process. Disruption of these important interactions could provide a mechanism for allosteric inhibition of IN. We present the highest resolution crystal structure of the IN core domain to date. We also present a crystal structure of the IN core domain in complex with sucrose which is bound at the dimer interface in a region that has previously been reported to bind integrase inhibitors.


Subject(s)
HIV Integrase Inhibitors/metabolism , HIV Integrase/chemistry , HIV Integrase/metabolism , HIV-1/enzymology , Sucrose/metabolism , Allosteric Regulation , Binding Sites , Crystallography, X-Ray , Drug Discovery , Glycerol/metabolism , HIV Integrase/genetics , HIV Integrase/isolation & purification , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/physiology , Models, Molecular , Protein Binding , Protein Multimerization , Protein Structure, Quaternary , Protein Structure, Tertiary , Virus Replication/drug effects
12.
J Med Chem ; 52(17): 5344-55, 2009 Sep 10.
Article in English | MEDLINE | ID: mdl-19663428

ABSTRACT

Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.


Subject(s)
Clofibric Acid/metabolism , Fatty Acid-Binding Proteins/metabolism , Hypolipidemic Agents/metabolism , Liver/metabolism , Animals , Binding Sites , Carboxylic Acids/chemistry , Clofibric Acid/chemistry , Clofibric Acid/pharmacology , Esters/chemistry , Fatty Acid-Binding Proteins/chemistry , Fenofibrate/analogs & derivatives , Fenofibrate/chemistry , Fenofibrate/metabolism , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Rats , Spectrometry, Fluorescence , Substrate Specificity , Temperature , Thermodynamics
13.
J Biol Chem ; 284(26): 17835-45, 2009 Jun 26.
Article in English | MEDLINE | ID: mdl-19389711

ABSTRACT

Oxidative protein folding in Gram-negative bacteria results in the formation of disulfide bonds between pairs of cysteine residues. This is a multistep process in which the dithiol-disulfide oxidoreductase enzyme, DsbA, plays a central role. The structure of DsbA comprises an all helical domain of unknown function and a thioredoxin domain, where active site cysteines shuttle between an oxidized, substrate-bound, reduced form and a DsbB-bound form, where DsbB is a membrane protein that reoxidizes DsbA. Most DsbA enzymes interact with a wide variety of reduced substrates and show little specificity. However, a number of DsbA enzymes have now been identified that have narrow substrate repertoires and appear to interact specifically with a smaller number of substrates. The transient nature of the DsbA-substrate complex has hampered our understanding of the factors that govern the interaction of DsbA enzymes with their substrates. Here we report the crystal structure of a complex between Escherichia coli DsbA and a peptide with a sequence derived from a substrate. The binding site identified in the DsbA-peptide complex was distinct from that observed for DsbB in the DsbA-DsbB complex. The structure revealed details of the DsbA-peptide interaction and suggested a mechanism by which DsbA can simultaneously show broad specificity for substrates yet exhibit specificity for DsbB. This mode of binding was supported by solution nuclear magnetic resonance data as well as functional data, which demonstrated that the substrate specificity of DsbA could be modified via changes at the binding interface identified in the structure of the complex.


Subject(s)
Escherichia coli Proteins/chemistry , Escherichia coli Proteins/metabolism , Escherichia coli/enzymology , Peptide Fragments/metabolism , Protein Disulfide-Isomerases/chemistry , Protein Disulfide-Isomerases/metabolism , Amino Acid Sequence , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Catalysis , Crystallography, X-Ray , Disulfides/metabolism , Escherichia coli Proteins/genetics , Magnetic Resonance Spectroscopy , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Disulfide-Isomerases/genetics , Sequence Homology, Amino Acid , Substrate Specificity
14.
J Biol Chem ; 283(47): 32452-61, 2008 Nov 21.
Article in English | MEDLINE | ID: mdl-18715864

ABSTRACT

DsbA is an enzyme found in the periplasm of Gram-negative bacteria that catalyzes the formation of disulfide bonds in a diverse array of protein substrates, many of which are involved in bacterial pathogenesis. Although most bacteria possess only a single essential DsbA, Neisseria meningitidis is unusual in that it possesses three DsbAs, although the reason for this additional redundancy is unclear. Two of these N. meningitidis enzymes (NmDsbA1 and NmDsbA2) play an important role in meningococcal attachment to human epithelial cells, whereas NmDsbA3 is considered to have a narrow substrate repertoire. To begin to address the role of DsbAs in the pathogenesis of N. meningitidis, we have determined the structure of NmDsbA3 to 2.3-A resolution. Although the sequence identity between NmDsbA3 and other DsbAs is low, the NmDsbA3 structure adopted a DsbA-like fold. Consistent with this finding, we demonstrated that NmDsbA3 acts as a thiol-disulfide oxidoreductase in vitro and is reoxidized by Escherichia coli DsbB (EcDsbB). However, pronounced differences in the structures between DsbA3 and EcDsbA, which are clustered around the active site of the enzyme, suggested a structural basis for the unusual substrate specificity that is observed for NmDsbA3.


Subject(s)
Neisseria meningitidis/enzymology , Oxidoreductases/chemistry , Protein Disulfide Reductase (Glutathione)/chemistry , Protein Disulfide Reductase (Glutathione)/physiology , Bacterial Proteins/chemistry , DNA/chemistry , Dithiothreitol/chemistry , Escherichia coli/metabolism , Escherichia coli Proteins/chemistry , Insulin/metabolism , Kinetics , Membrane Proteins/chemistry , Neisseria meningitidis/chemistry , Oxygen/chemistry , Protein Conformation , Protein Disulfide-Isomerases/chemistry , Protein Structure, Secondary , Recombinant Proteins/chemistry , Substrate Specificity
15.
J Comput Aided Mol Des ; 19(5): 301-17, 2005 May.
Article in English | MEDLINE | ID: mdl-16184433

ABSTRACT

While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford's GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186-194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140-149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.


Subject(s)
Computer Simulation , HIV Integrase/chemistry , Models, Molecular , Virus Integration , Amino Acid Sequence , Base Sequence , Conserved Sequence , DNA, Viral/chemistry , DNA, Viral/genetics , Dimerization , HIV Infections/genetics , HIV Infections/virology , HIV-1/chemistry , HIV-1/genetics , HIV-1/physiology , Humans , Macromolecular Substances , Nucleic Acid Conformation , Protein Conformation , Protein Structure, Tertiary
16.
J Biol Chem ; 280(18): 17769-76, 2005 May 06.
Article in English | MEDLINE | ID: mdl-15722357

ABSTRACT

Intestinal fatty acid-binding protein (I-FABP) is a small protein that binds long-chain dietary fatty acids in the cytosol of the columnar absorptive epithelial cells (enterocytes) of the intestine. The binding cavity of I-FABP is much larger than is necessary to bind a fatty acid molecule, which suggests that the protein may be able to bind other hydrophobic and amphipathic ligands such as lipophilic drugs. Herein we describe the binding of three structurally diverse lipophilic drugs, bezafibrate, ibuprofen (both R- and S-isomers) and nitrazepam to I-FABP. The rank order of affinity for I-FABP determined for these compounds was found to be R-ibuprofen approximately bezafibrate > S-ibuprofen >> nitrazepam. The binding affinities were not directly related to aqueous solubility or partition coefficient of the compounds; however, the freely water-soluble drug diltiazem showed no affinity for I-FABP. Drug-I-FABP interaction interfaces were defined by analysis of chemical shift perturbations in NMR spectra, which revealed that the drugs bound within the central fatty acid binding cavity. Each drug participated in a different set of interactions within the cavity; however, a number of common contacts were observed with residues also involved in fatty acid binding. These data suggest that the binding of non-fatty acid lipophilic drugs to I-FABP may increase the cytosolic solubility of these compounds and thereby facilitate drug transport from the intestinal lumen across the enterocyte to sites of distribution and metabolism.


Subject(s)
Carrier Proteins/metabolism , Lipid Metabolism , Pharmaceutical Preparations/metabolism , Animals , Binding Sites/physiology , Carrier Proteins/chemistry , Fatty Acid-Binding Proteins , Pharmaceutical Preparations/chemistry , Rats
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