The 1.8-Å Crystal Structure of α1-Acid Glycoprotein (Orosomucoid) Solved by UV RIP Reveals the Broad Drug-Binding Activity of This Human Plasma Lipocalin

Schonfeld, D.L.; Ravelli, Raimond B. G.; Muêller, U.; Skerra, Arne

doi:10.1016/j.jmb.2008.09.020

Cited by 143 publications

(201 citation statements)

References 75 publications

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“…Docking studies have shown that the neutral diazepam binds to lobe I, while progesterone -to lobe II. (48). The A variant has the same overall folding as the F1*S variant, but differs in the amino acid sequence and binding site topology.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Zhivkova

2017

J Pharm Pharm Sci

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Purpose. Binding of drugs to plasma proteins is a common physiological occurrence which may have a profound effect on both pharmacokinetics and pharmacodynamics. The early prediction of plasma protein binding (PPB) of new drug candidates is an important step in drug development process. The present study is focused on the development of quantitative structure -pharmacokinetics relationship (QSPkR) for the negative logarithm of the free fraction of the drug in plasma (pf u ) of basic drugs. Methods. A dataset includes 220 basic drugs, which chemical structures are encoded by 176 descriptors. Genetic algorithm, stepwise regression and multiple linear regression are used for variable selection and model development. Predictive ability of the model is assessed by internal and external validation. Results. A simple, significant, interpretable and predictive QSPkR model is constructed for pf u of basic drugs. It is able to predict 59% of the drugs from an external validation set within the 2-fold error of the experimental values with squared correlation coefficient of prediction 0.532, geometric mean fold error (GMFE) 1.94 and mean absolute error (MAE) 0.17. Conclusions. PPB of basic drugs is favored by the lipophilicity, the presence of aromatic C-atoms (either non-substituted, or involved in bridged aromatic systems) and molecular volume. The fraction ionized as a base f B and the presence of quaternary Catoms contribute negatively to PPB. A short checklist of criteria for high PPB is defined, and an empirical rule for distinguishing between low, high and very high plasma protein binders is proposed based. This rule allows correct classification of 69% of the very high binders, 71% of the high binders and 91% of the low binders in plasma.

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Section: Discussionmentioning

confidence: 99%

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Zhivkova

2017

J Pharm Pharm Sci

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“…1C) was chosen as the mouse LepR-LBD structure. The X-ray crystal structure of human ORM (i.e., AGP) was taken from PDB (PDB entry code 3KQ0) (35). Both structures were then prepared with the Protein Preparation Wizard workflow in Maestro, version 9.3 (Schrödinger, L.L.C., New York, NY).…”

Section: Molecular Modelingmentioning

confidence: 99%

The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway

et al. 2016

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The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders.

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“…The observation that molecules that are small compared to the HN tetramer, or that are fixed to the glycan array at a spacing of approximately 0.5 nm (calculated from reference 2), are more susceptible to N than glycoproteins of a size comparable to HN whose glycans may not be anchored to the protein at distances that allow engagement of two or more active sites (calculated from Protein Data Bank [PDB] 3BX6 [33]) supports this idea. However, the observation that digestion of bFetuin with proteinase K does not restore small-molecule-like susceptibility suggests that other factors are also in effect.…”

Section: Composition Of Hpivmentioning

confidence: 91%

Fixation of Oligosaccharides to a Surface May Increase the Susceptibility to Human Parainfluenza Virus 1, 2, or 3 Hemagglutinin-Neuraminidase

Tappert

Smith

Air

2011

J Virol

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The hemagglutinin-neuraminidase (HN) protein of human parainfluenza viruses (hPIVs) both binds (H) and cleaves (N) oligosaccharides that containIn the present study, we tested the binding specificity of hPIV2 on the Consortium for Functional Glycomics' glycan array and found that hPIV2 binds to oligosaccharides containing the same motif. We determined the specificities of N on red blood cells, soluble smallmolecule and glycoprotein substrates, and the glycan array and compared them to the specificities of H. hPIV2 and -3, but not hPIV1, cleaved their ligands on red blood cells. hPIV1, -2, and -3 cleaved their NeuAc␣2-3 ligands on the glycan array; hPIV2 and -3 also cleaved NeuAc␣2-6 ligands bound by influenza A virus. While all three HNs exhibited similar affinities for all cleavable soluble substrates, their activities were 5-to 10-fold higher on small molecules than on glycoproteins. In addition, some soluble glycoproteins were not cleaved, despite containing oligosaccharides that were cleaved on the glycan array. We conclude that the susceptibility of an oligosaccharide substrate to N increases when the substrate is fixed to a surface. These findings suggest that HN may undergo a conformational change that activates N upon receptor binding at a cell surface.

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The 1.8-Å Crystal Structure of α1-Acid Glycoprotein (Orosomucoid) Solved by UV RIP Reveals the Broad Drug-Binding Activity of This Human Plasma Lipocalin

Cited by 143 publications

References 75 publications

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway

Fixation of Oligosaccharides to a Surface May Increase the Susceptibility to Human Parainfluenza Virus 1, 2, or 3 Hemagglutinin-Neuraminidase

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