Biochemical analysis of West Nile virus methyltransferase shows that the single SAM-binding site donates methyl groups to both N7 and 2′-O positions of the viral RNA cap, the GTP-binding pocket functions only during the 2′-O methylation, and two distinct sets of amino acids in the RNA-binding site are required for the N7 and 2′-O methylations. These results demonstrate that flavivirus methyltransferase catalyzes two cap methylations through a substrate-repositioning mechanism. In this mechanism,

guanine N7 of substrate GpppA-RNA is first positioned to SAM to generate m(7) GpppA-RNA, after which the m(7) G moiety is repositioned to the GTP-binding pocket to register the 2′-OH of the adenosine with SAM, generating m(7) GpppAm-RNA. Because N7 cap methylation is essential for viral learn more replication, inhibitors designed to block the pocket identified for the N7 cap methylation could be developed for flavivirus therapy.”
“AMPA receptors mediate the majority of fast synaptic transmission

and underlie several forms of synaptic plasticity. AMPARs also have an important role in several neuronal pathologies. Therefore, https://www.selleckchem.com/products/3-methyladenine.html studying the structure and function of these receptors is important for understanding general mechanisms of synaptic transmission as well as for the development of new therapies. A recent study identified the apparent binding sites for GYKI 53655 (GYKI) and CP-465,022 (CP) at the interface between the glutamate binding core and the transmembrane domains. The emerging role of transmembrane AMPA receptor regulatory proteins (TARPs) in AMPAR function raises the possibility that the antagonism of these receptors is also affected by TARPs such as stargazin. Here we compare the antagonism of the competitive antagonist CNQX and the negative allosteric modulators GYKI, and CP in the absence and presence of stargazin. We found that stargazin decreases the apparent affinity of GluR1 for CNQX, which is most likely explained the by a partial agonistic effect of CNQX. In contrast, stargazin increases the affinity for GYKI, and has only a small effect on CP binding.

Because inhibition of recently described GYKI insensitive receptors is restored by co-expression with stargazin, our data suggest that the identified residues do not constitute the full GYKI binding site. We could show that the ectodomain of stargazin controls the change in agonist sensitivity. Mutations in the identified binding regions for GYKI and CP dramatically reduced surface expression. Our data provides further evidence that TARPs alter the conformation of pore-forming subunits and thereby affects antagonist interaction. (C) 2008 Elsevier Ltd. All fights reserved.”
“The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown.