The engineered β-lactoglobulin with complementarity to the chlorpromazine chiral conformers

Loch, J.I.; Bonarek, Piotr; Tworzydło, Magdalena; Lazinska, I.; Szydłowska, Joanna; Lipowska, Joanna; Rzęsikowska, Katarzyna; Lewiński, K.

doi:10.1016/j.ijbiomac.2018.03.074

Cited by 10 publications

(24 citation statements)

References 51 publications

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“…At least one nanomaterial-based biosensor exists for organophosphorus pesticides, using acetylcholinesterase and gold nanoparticles [37]. BLG is amenable to nanoparticle formation [38], as well as to reengineering to bind selected ligands, such as a dopamine antagonist [39]. BLG has the additional property of being able to bind different ligands with good affinity with a single binding site, which can be exploited in biosensor design.…”

Section: Discussionmentioning

confidence: 99%

Docking and Molecular Dynamics Predictions of Pesticide Binding to the Calyx of Bovine β-Lactoglobulin

Cortés-Hernández

Nuñez

Domínguez-Ramírez

2020

IJMS

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Pesticides are used extensively in agriculture, and their residues in food must be monitored to prevent toxicity. The most abundant protein in cow’s milk, β-lactoglobulin (BLG), shows high affinity for diverse hydrophobic ligands in its central binding pocket, called the calyx. Several of the most frequently used pesticides are hydrophobic. To predict if BLG may be an unintended carrier for pesticides, we tested its ability to bind 555 pesticides and their isomers, for a total of 889 compounds, in a rigid docking screen. We focused on the analysis of 60 unique molecules belonging to the five pesticide classes defined by the World Health Organization, that docked into BLG’s calyx with ΔGs ranging from −8.2 to −12 kcal mol−1, chosen by statistical criteria. These “potential ligands” were further analyzed using molecular dynamic simulations, and the binding energies were explored with Molecular Mechanics/Generalized Born/Surface Area (MMGBSA). Hydrophobic pyrethroid insecticides, like cypermethrin, were found to bind as deeply and tightly into the calyx as BLG’s natural ligand, palmitate; while polar compounds, like paraquat, were expelled. Our results suggest that BLG could be a carrier for pesticides, in particular for pyrethroid insecticides, allowing for their accumulation in cow’s milk beyond their solubility restrictions. This analysis opens possibilities for pesticide biosensor design based on BLG.

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Section: Discussionmentioning

confidence: 99%

Docking and Molecular Dynamics Predictions of Pesticide Binding to the Calyx of Bovine β-Lactoglobulin

Cortés-Hernández

Nuñez

Domínguez-Ramírez

2020

IJMS

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“…Although Davis and Dubos (1947) noted that βLg bound about half as much oleic acid as serum albumin, it was Groves et al (1951) who showed that 2 mol/mol of sodium dodecyl sulfate not only bound but had a stabilizing effect on thermal denaturation. Since then, a large number of ligands for βLg has been identified and that number is still increasing ( Sawyer, 2003 ; Tromelin and Guichard, 2006 ; Cherrier et al, 2013 ; Le Maux et al, 2014 ; Loch et al, 2015 , 2018 ). To date, the only definitive ligand binding site is within the central calyx despite there being several experimental studies indicating that alternative sites may exist ( Frapin et al, 1993 ; Dufour et al, 1994 ; Lange et al, 1998 ; Narayan and Berliner, 1998 ; Lübke et al, 2002 ; Yang et al, 2008 , 2009 ; Edwards and Jameson, 2020 ).…”

Section: β-Lactoglobulinmentioning

confidence: 99%

β-Lactoglobulin and Glycodelin: Two Sides of the Same Coin?

Sawyer

2021

Front. Physiol.

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The two lipocalins, β-lactoglobulin (βLg) and glycodelin (Gd), are possibly the most closely related members of the large and widely distributed lipocalin family, yet their functions appear to be substantially different. Indeed, the function of β-lactoglobulin, a major component of ruminant milk, is still unclear although neonatal nutrition is clearly important. On the other hand, glycodelin has several specific functions in reproduction conferred through distinct, tissue specific glycosylation of the polypeptide backbone. It is also associated with some cancer outcomes. The glycodelin gene, PAEP, reflecting one of its names, progestagen-associated endometrial protein, is expressed in many though not all primates, but the name has now also been adopted for the β-lactoglobulin gene (HGNC, www.genenames.org). After a general overview of the two proteins in the context of the lipocalin family, this review considers the properties of each in the light of their physiological functional significance, supplementing earlier reviews to include studies from the past decade. While the biological function of glycodelin is reasonably well defined, that of β-lactoglobulin remains elusive.

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“…Crystals of this variant had unusual orthorhombic symmetry P2 1 2 1 2 1 (Table S2 at https://ojs.ptbioch.edu.pl/index.php/abp/) with protein dimer in the asymmetric unit. The binding pocket in the I56F variant (Bonarek et al, 2020) and its derivatives I56F/L39A and I56F/L39A/M107F (Loch et al, 2018) has a permanently reduced length. The large side chain of phenylalanine in position 56 prevents aliphatic ligands and tetracaine from binding in the modified binding pocket.…”

Section: Structure Of L39k and F105a Mutantsmentioning

confidence: 99%

“…Human lipocalins are usually modified by randomization of flexible loops surrounding β-barrel to create highly specific proteins with potential medical applications called Anticalins (Rothe & Skerra, 2018). In our studies, local site-directed mutagenesis was used to change the geometry of the BLG ligand binding pocket and therefore change its ligand preferences (Loch et al, 2018;Bonarek et al, 2020). Detailed physicochemical characteristics of seven new lactoglobulin mutants (L39Y, I56F, L58F, V92F, V92Y, F105L, and M107L) as well as crystal structure of five of these variants and their complexes with selected fatty acids have been published elsewhere (Bonarek et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Interactions of new lactoglobulin variants with tetracaine: crystallographic studies of ligand binding to lactoglobulin mutants possessing single substitution in the binding pocket

et al. 2021

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β-Lactoglobulin (BLG) like other lipocalins can be modified by mutagenesis to re-direct its ligand binding properties. Local site-directed mutagenesis was used to change the geometry of the BLG ligand binding pocket and therefore change BLG ligand preferences. The presented studies are focused on previously described mutants L39Y, I56F, L58F, F105L, and M107L and two new BLG variants, L39K and F105A, and their interactions with local anesthetic drug tetracaine. Binding of tetracaine to BLG mutants was investigated by X-ray crystallography. Structural analysis revealed that for tetracaine binding, the shape of the binding pocket seems to be a more important factor than the substitutions influencing the number of interactions. Analyzed BLG mutants can be classified according to their binding properties to variants: capable of binding tetracaine in the β-barrel (L58F, M107L); capable of accommodating tetracaine on the protein surface (I56F) and unable to bind tetracaine (F105L). Variants L39K, L39Y, and F105A, had a binding pocket blocked by endogenous fatty acids. The new tetracaine binding site was found in the I56F variant. The site localized on the surface near Arg124 and Trp19 was previously predicted by in silico studies and was confirmed in the crystal structure.

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The engineered β-lactoglobulin with complementarity to the chlorpromazine chiral conformers

Cited by 10 publications

References 51 publications

Docking and Molecular Dynamics Predictions of Pesticide Binding to the Calyx of Bovine β-Lactoglobulin

Docking and Molecular Dynamics Predictions of Pesticide Binding to the Calyx of Bovine β-Lactoglobulin

β-Lactoglobulin and Glycodelin: Two Sides of the Same Coin?

Interactions of new lactoglobulin variants with tetracaine: crystallographic studies of ligand binding to lactoglobulin mutants possessing single substitution in the binding pocket

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