Testosterone meets albumin – the molecular mechanism of sex hormone transport by serum albumins

Czub, M.P.; Venkataramany, Barat S.; Majorek, K.A.; Handing, K.B.; Porebski, P.J.; Beeram, Sandya; Suh, Kwang I.; Woolfork, Ashley G.; Hage, David S.; Shabalin, I.G.; Minor, W.

doi:10.1039/c8sc04397c

Cited by 41 publications

(35 citation statements)

References 70 publications

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“…However, in the alternative orientation one of the four rings of dexamethasone was outside strong electron density, and the compound did not form any hydrogen bonds to the protein, clearly supporting the chosen conformation. The mode of binding of dexamethasone in the chosen orientation is very similar to that observed in the very well defined electron density for the structurally similar testosterone (Czub et al, 2019). ADP, RSR and RSCC values for the dexamethasone molecule are reported in Table 1.…”

Section: Structure Of Serum Albumin In Complex With Dexamethasonesupporting

confidence: 68%

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Shabalin

Czub

Majorek

et al. 2020

Int Union Crystallogr J

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Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Here, the first structure of serum albumin in complex with dexamethasone is reported. Dexamethasone binds to drug site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with an analysis of publicly available clinical data from Wuhan and suggests that an adjustment of the dexamethasone regimen should be further investigated as a strategy for patients affected by two major COVID-19 risk factors: low albumin levels and diabetes.

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Section: Structure Of Serum Albumin In Complex With Dexamethasonesupporting

confidence: 68%

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Shabalin

Czub

Majorek

et al. 2020

Int Union Crystallogr J

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“…. The presence of HSA in the final product, raises concerns in terms of products safety since HSA transports a number of other proteins or protein segments, which can cause adverse reactions and be potentially harmful .…”

Section: Resultsmentioning

confidence: 99%

Human chorionic gonadotrophin pharmaceutical formulations of urinary origin display high levels of contaminant proteins–A label‐free quantitation proteomics study

Panić-Janković

Mitulović

2019

Electrophoresis

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To determine whether there is a measurable protein background in different formulations of urinary and recombinant human chorionic gonadotropin (hCG). Primary outcome measures: identification of contaminant proteins in urinary‐derived formulations of hCG; secondary outcome measures: quantitative values of contaminant proteins in different batches of urinary –derived hCG formulations. It was found that urinary‐derived batches have high presence of contaminant proteins beside the active substance. The relative amount of contaminant proteins and hCG differs strongly between different batches.

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“…Moreover, DS7 is classified as one of the most conserved drug-binding sites between ESA and HSA (9). For example, the residue conservation in this site was shown to result in similar testosterone-binding properties of this site in albumin from both species (15). Similarly, 14 out of 15 residues involved in dexamethasone binding to ESA are conserved in HSA (Fig.…”

Section: Structure Of Serum Albumin In Complex With Dexamethasonementioning

confidence: 96%

“…Similarly, dexamethasone overlaps with the testosterone molecule (Fig. 2C), which is the only steroid for which a structure of a complex with albumin has been determined (15). Testosterone is suspected of playing a critical role in driving the pronounced excess of COVID-19 lethality in male patients (23), and low testosterone levels predict adverse clinical outcomes (24).…”

Section: Competing Compounds and Albumin Glycation May Impair Dexametmentioning

confidence: 99%

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Shabalin

Czub

Majorek

et al. 2020

Preprint

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Dexamethasone, a widely used corticosteroid, has recently been reported as the first drug to increase the survival chances of patients with severe COVID-19. Therapeutic agents, including dexamethasone, are mostly transported through the body by binding to serum albumin. Herein, we report the first structure of serum albumin in complex with dexamethasone. We show that it binds to Drug Site 7, which is also the binding site for commonly used nonsteroidal anti-inflammatory drugs and testosterone, suggesting potentially problematic binding competition. This study bridges structural findings with our analysis of publicly available clinical data from Wuhan and suggests that an adjustment of dexamethasone regimen should be considered for patients affected by two major COVID-19 risk-factors: low albumin levels and diabetes.One Sentence SummaryStructure of serum albumin with dexamethasone reveals why the drug may not always help COVID-19 patients.

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Testosterone meets albumin – the molecular mechanism of sex hormone transport by serum albumins

Abstract: The first albumin structure in complex with testosterone and the hormone's binding affinity measured with two methods.

Cited by 41 publications

References 70 publications

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

Human chorionic gonadotrophin pharmaceutical formulations of urinary origin display high levels of contaminant proteins–A label‐free quantitation proteomics study

Molecular determinants of vascular transport of dexamethasone in COVID-19 therapy

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