The solution structure of the unbound IgG Fc receptor CD64 resembles its crystal structure:Implications for function

FcγRI (CD64) is the only high-affinity Fcγ receptor found on monocytes, macrophages, eosinophils, neutrophils and dendritic cells. It binds immunoglobulin G (IgG) antibody-antigen complexes at its Fc region to trigger key immune responses. CD64 contains three immunoglobulin-fold extracellular domains (D1, D2 and D3) and a membrane-spanning region. Despite the importance of CD64, no solution structure for this is known to date. To investigate this, we used analytical ultracentrifugation, small-angle X-ray scattering, and atomistic modelling. Analytical ultracentrifugation revealed that CD64 was monomeric with a sedimentation coefficient s020,w of 2.53 S, together with some dimer. Small-angle X-ray scattering showed that its radius of gyration RG was 3.3–3.4 nm and increased at higher concentrations to indicate low dimerization. Monte Carlo modelling implemented in the SASSIE-web package generated 279,162 physically-realistic trial CD64 structures. From these, the scattering best-fit models at the lowest measured concentrations that minimised dimers revealed that the D1, D2 and D3 domains were structurally similar to those seen in three CD64 crystal structures, but showed previously unreported flexibility between D1, D2 and D3. Despite the limitations of the scattering data, the superimposition of the CD64 solution structures onto crystal structures of the IgG Fc-CD64 complex showed that the CD64 domains do not sterically clash with the IgG Fc region, i.e. the solution structure of CD64 was sufficiently compact to allow IgG to bind to its high-affinity Fcγ receptor. This improved understanding may result in novel approaches to inhibit CD64 function, and opens the way for the solution study of the full-length CD64-IgG complex.</p

The solution structure of the unbound IgG Fc receptor CD64 resembles its crystal structure: Implications for function

FcγRI (CD64) is the only high-affinity Fcγ receptor found on monocytes, macrophages, eosinophils, neutrophils and dendritic cells. It binds immunoglobulin G (IgG) antibody-antigen complexes at its Fc region to trigger key immune responses. CD64 contains three immunoglobulin-fold extracellular domains (D1, D2 and D3) and a membrane-spanning region. Despite the importance of CD64, no solution structure for this is known to date. To investigate this, we used analytical ultracentrifugation, small-angle X-ray scattering, and atomistic modelling. Analytical ultracentrifugation revealed that CD64 was monomeric with a sedimentation coefficient s020,w of 2.53 S, together with some dimer. Small-angle X-ray scattering showed that its radius of gyration RG was 3.3–3.4 nm and increased at higher concentrations to indicate low dimerization. Monte Carlo modelling implemented in the SASSIE-web package generated 279,162 physically-realistic trial CD64 structures. From these, the scattering best-fit models at the lowest measured concentrations that minimised dimers revealed that the D1, D2 and D3 domains were structurally similar to those seen in three CD64 crystal structures, but showed previously unreported flexibility between D1, D2 and D3. Despite the limitations of the scattering data, the superimposition of the CD64 solution structures onto crystal structures of the IgG Fc-CD64 complex showed that the CD64 domains do not sterically clash with the IgG Fc region, i.e. the solution structure of CD64 was sufficiently compact to allow IgG to bind to its high-affinity Fcγ receptor. This improved understanding may result in novel approaches to inhibit CD64 function, and opens the way for the solution study of the full-length CD64-IgG complex

Insights into the Roles of Midazolam in Cancer Therapy

With its high worldwide mortality and morbidity, cancer has gained increasing attention and novel anticancer drugs have become the focus for cancer research. Recently, studies have shown that most anesthetic agents can influence the activity of tumor cells. Midazolam is a γ-aminobutyric acid A (GABAA) receptor agonist, used widely for preoperative sedation and as an adjuvant during neuraxial blockade. Some studies have indicated the potential for midazolam as a novel therapeutic cancer drug; however, the mechanism by which midazolam affects cancer cells needs to be clarified. This systematic review aims to summarize the progress in assessing the molecular mechanism of midazolam as an anticancer agent

An Improved Grid-connected Pre-Synchronization Method based on Virtual Synchronous Generator Control in Power Conversion System

Under the background of vigorously promoting the construction of new power system，the power conversion system(PCS) plays an important role to transfer high reliable electrical power quality to grid. However, the system is sensitive to the voltage deviation on both side of point of common coupling(PCC) when switching from off-grid mode to grid-connected mode directly, it leads to surge currents or even threaten system stability.In this paper, an improved grid-connected pre-synchronization method for smooth grid connection is proposed. The system adds a pre-synchronization module on the basis of virtual synchronous generator(VSG) control to synchronize the voltage between the PCS and the grid. In addition, a slope control unit is introduced to further avoid the potential surge current problem at the moment of grid connection. Finally, the experimental results of simulation is verified the effectiveness and feasibility of the proposed scheme