Elucidation of the ATP7B N-Domain Mg2+-ATP Coordination Site and Its Allosteric Regulation

The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecular modeling tools and surface plasmonic resonance to study the function of the ATP7B protein, which is impaired in the Wilson disease. Experimentally validated in silico models allow the elucidation in the Nucleotide binding domain (N-domain) of the Mg2+-ATP coordination site and answer to the controversial role of the Mg2+ ion in the nucleotide binding process. The analysis of protein motions revealed a substantial effect on a long flexible loop branched to the N-domain protein core. We demonstrated the capacity of the loop to disrupt the interaction between Mg2+-ATP complex and the N-domain and propose a role for this loop in the allosteric regulation of the nucleotide binding process

Contribution of molecular modeling to the study of human disease : Application to ATP7B transporter and receptor 5HT2B

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Contribution de la modélisation moléculaire à l’étude de pathologies humaines : Application au transporteur ATP7B et au récepteur 5HT2B

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Contribution de la modélisation moléculaire à l'étude de pathologies humaines (Application au transporteur ATP7B et au récepteur 5HT2B)

Pas de résumé en françaisPas de résumé en anglaisPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Apport de la modélisation moléculaire en diagnostic génétique (application à la maladie de Wilson)

PARIS-BIUP (751062107) / SudocSudocFranceF

Accuracy of citrulline, I-FABP and D-lactate in the diagnosis of acute mesenteric ischemia

International audienceEarly diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI-citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients-50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0-26.0) vs. 23.3 μmol/L (18.3-29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58-0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers