Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Lim, Sing Mei; Chen, Dan; Teo, Hsiangling; Roos, A.K.; Jansson, Anna; Nyman, T.; Tresaugues, L.; Pervushin, Konstantin; Nordlund, P.

doi:10.1194/jlr.m035410

Cited by 22 publications

(54 citation statements)

References 54 publications

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“…This study was the first to thoroughly examine the binding of a variety of endogenous bioactive lipids, phytocannabinoids, and synthetic ligands to L‐PGDS. Δ 1–28 L‐PGDS displayed the highest affinity for lipids bearing free carboxylate moieties while low or no affinity for ligands lacking this functional group, consistent with structural data demonstrating electrostatic interactions between the carboxylate groups of ligands and residues lining the binding cavity of L‐PGDS (Lim et al, ). Contrary to our hypothesis, Δ 1–28 L‐PGDS displayed weak or no affinity for a variety of endogenous ligands including the endocannabinoids and NAE, suggesting that other proteins in the CSF may bind and transport these lipids.…”

Section: Resultssupporting

confidence: 77%

Lipocalin‐Type Prostaglandin D Synthase Is a Novel Phytocannabinoid‐Binding Protein

Elmes

Volpe

d’Oelsnitz

et al. 2018

Lipids

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Lipocalin-type prostaglandin D synthase (L-PGDS; EC:5.3.99.2) is an enzyme with dual functional roles as a prostaglandin D -synthesizing enzyme and as an extracellular transporter for diverse lipophilic compounds in the cerebrospinal fluid (CSF). Transport of hydrophobic endocannabinoids is mediated by serum albumin in the blood and intracellularly by the fatty acid binding proteins, but no analogous transport mechanism has yet been described in CSF. L-PGDS has been reported to promiscuously bind a wide variety of lipophilic ligands and is among the most abundant proteins found in the CSF. Here, we examine the binding of several classes of endogenous and synthetic ligands to L-PGDS. Endocannabinoids exhibited low affinity toward L-PGDS, while cannabinoid metabolites and synthetic cannabinoids displayed higher affinities for L-PGDS. These results indicate that L-PGDS is unlikely to function as a carrier for endocannabinoids in the CSF, but it may bind and transport a subset of cannabinoids.

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Section: Resultssupporting

confidence: 77%

Lipocalin‐Type Prostaglandin D Synthase Is a Novel Phytocannabinoid‐Binding Protein

Elmes

Volpe

d’Oelsnitz

et al. 2018

Lipids

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“…Although there are several complex structures between L‐PGDS and ligands, the crystal structures of human L‐PGDS complexed with fatty acids (oleic acid and palmitic acid, code: 3O19, 3O22, 3O2Y) [29], substrate analog U‐44069 (code: 4IMO) [28], and the solution structure of mouse L‐PGDS complexed with substrate analog U‐46619 (code: 2KTD), the only available information on the complex structure between L‐PGDS and the lipophilic ligand utilized here is the complex of mouse L‐PGDS and U‐46619. It is assumed that human L‐PGDS examined in the present study show a similar thermodynamic behaviors for binding U‐46619 to mouse L‐PGDS on the basis of 75–80% sequence homology between the two L‐PGDSs.…”

Section: Discussionmentioning

confidence: 99%

Fine‐tuned broad binding capability of human lipocalin‐type prostaglandin D synthase for various small lipophilic ligands

et al. 2014

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Edited by Miguel De la Rosa Keywords:Binding thermodynamic Driving force Enthalpy-entropy compensation Hydrophobic effect Isothermal titration calorimetry Lipocalin-type prostaglandin D synthase Protein-ligand interaction a b s t r a c tThe hydrophobic cavity of lipocalin-type prostaglandin D synthase (L-PGDS) has been suggested to accommodate various lipophilic ligands through hydrophobic effects, but its energetic origin remains unknown. We characterized 18 buffer-independent binding systems between human L-PGDS and lipophilic ligands using isothermal titration calorimetry. Although the classical hydrophobic effect was mostly detected, all complex formations were driven by favorable enthalpic gains. Gibbs energy changes strongly correlated with the number of hydrogen bond acceptors of ligand. Thus, the broad binding capability of L-PGDS for ligands should be viewed as hydrophilic interactions delicately tuned by enthalpy-entropy compensation using combined effects of hydrophilic and hydrophobic interactions.

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“…Molecular dynamics studies on lipocalins indicate that the overall conformation of the beta-barrel is maintained while larger changes occur for the open-end beta-hairpin loops55. Confirmed by NMR, these large conformational changes are present for open-end beta-hairpin loops in bound and unbound lipocalin structures56. Some regions were omitted from ANM calculations to minimize extraneous perturbations outside the open-end beta-hairpin loops.…”

Section: Methodsmentioning

confidence: 99%

Substrate prediction of Ixodes ricinus salivary lipocalins differentially expressed during Borrelia afzelii infection

Valdés

Cabezas-Cruz

Šíma

et al. 2016

Sci Rep

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Evolution has provided ticks with an arsenal of bioactive saliva molecules that counteract host defense mechanisms. This salivary pharmacopoeia enables blood-feeding while enabling pathogen transmission. High-throughput sequencing of tick salivary glands has thus become a major focus, revealing large expansion within protein encoding gene families. Among these are lipocalins, ubiquitous barrel-shaped proteins that sequester small, typically hydrophobic molecules. This study was initiated by mining the Ixodes ricinus salivary gland transcriptome for specific, uncharacterized lipocalins: three were identified. Differential expression of these I. ricinus lipocalins during feeding at distinct developmental stages and in response to Borrelia afzelii infection suggests a role in transmission of this Lyme disease spirochete. A phylogenetic analysis using 803 sequences places the three I. ricinus lipocalins with tick lipocalins that sequester monoamines, leukotrienes and fatty acids. Both structural analysis and biophysical simulations generated robust predictions showing these I. ricinus lipocalins have the potential to bind monoamines similar to other tick species previously reported. The multidisciplinary approach employed in this study characterized unique lipocalins that play a role in tick blood-feeding and transmission of the most important tick-borne pathogen in North America and Eurasia.

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Structural and dynamic insights into substrate binding and catalysis of human lipocalin prostaglandin D synthase

Cited by 22 publications

References 54 publications

Lipocalin‐Type Prostaglandin D Synthase Is a Novel Phytocannabinoid‐Binding Protein

Lipocalin‐Type Prostaglandin D Synthase Is a Novel Phytocannabinoid‐Binding Protein

Fine‐tuned broad binding capability of human lipocalin‐type prostaglandin D synthase for various small lipophilic ligands

Substrate prediction of Ixodes ricinus salivary lipocalins differentially expressed during Borrelia afzelii infection

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