The molecular bases for the association of FHR-1 with atypical hemolytic uremic syndrome and other diseases.

Factor H-related proteins (FHRs) are a group of partly characterized complement proteins that are thought to promote complement activation by competing binding of factor H (FH) to surface-bound C3b. Among them, FHR-1 is remarkable because is associated with atypical hemolytic uremic syndrome (aHUS) and other important diseases. Using a combination of biochemical, immunological, nuclear magnetic resonance and computational approaches, we have characterized a series of FHR-1 mutants (including two associated with aHUS) and have unraveled the molecular bases of the so-called de-regulation activity of FHR-1. In contrast with FH, FHR-1 lacks the capacity to bind sialic acids, which prevents C3b-binding competition between FH and FHR-1 in host cell surfaces. aHUS-associated FHR-1 mutants are pathogenic because they have acquired the capacity to bind sialic acids, which increases FHR-1 avidity for surface-bound C3-activated fragments and results in C3b-binding competition with FH. FHR-1 binds to native C3, in addition to C3b, iC3b and C3dg. This unexpected finding suggests that the mechanism by which surface-bound FHR-1 promotes complement activation is the attraction of native C3 to the cell surface. Whilst C3b-binding competition with FH is limited to aHUS-associated mutants, all surface-bound FHR-1 promote complement activation, which is delimited by the FHR-1/FH activity ratio. Our data indicate that the FHR-1 de-regulation activity is important to sustain complement activation and C3 deposition at complement activating surfaces. They also support that abnormally elevated FHR-1/FH activity ratios would perpetuate a pathological complement dysregulation at complement activating surfaces, which may explain the association of FHR-1 quantitative variations with diseases.

Detection of Metabolite-Protein Interactions in Complex Biological Samples by High-Resolution Relaxometry: Towards Interactomics by NMR

In this manuscript, we introduce an NMR method to investigate the interaction of metabolites and other small molecules with proteins in biological fluids. Our approach, based on high-resolution relaxometry identifies the interaction of small molecules with proteins in blood serum and is used for the quantitative analysis of binding competition <i>in situ</i>.

Detection of Metabolite-Protein Interactions in Complex Biological Samples by High-Resolution Relaxometry: Towards Interactomics by NMR

In this manuscript, we introduce an NMR method to investigate the interaction of metabolites and other small molecules with proteins in biological fluids. Our approach, based on high-resolution relaxometry identifies the interaction of small molecules with proteins in blood serum and is used for the quantitative analysis of binding competition <i>in situ</i>.

Detection of Metabolite-Protein Interactions in Complex Biological Samples by High-Resolution Relaxometry: Towards Interactomics by NMR

In this manuscript, we introduce an NMR method to investigate the interaction of metabolites and other small molecules with proteins in biological fluids. Our approach, based on high-resolution relaxometry identifies the interaction of small molecules with proteins in blood serum and is used for the quantitative analysis of binding competition <i>in situ</i>.

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

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.

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

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.