Depending on the mAb, changes were beneficial, neutral, or detrimental, as measured by the ability of the serum from immunized mice to inhibit bacterial adherence to human salivary agglutinin by a BIAcore surface plasmon resonance assay. The current study further defined changes
in the host response that result from immunization with IC containing beneficial mAbs, and evaluated mechanisms by which beneficial immunomodulation could occur in this system. Immunomodulatory effects varied depending upon genetic background, with differing results in C57BL/6 and BALB/c mice. Desirable effects Adavosertib following IC immunization were observed in the absence of activating FcRs in BALB/c Fcer1g transgenic mice. mAb F(ab’)(2) mediated desirable changes similar to those observed using intact IgG. Sera from IC-immunized BALB/c mice that were better able to inhibit bacterial adherence demonstrated an increase in Abs able to compete with an adherence-inhibiting anti-P1 mAb, and binding of a beneficial immumomodulatory LY3039478 order mAb to S. mutans increased exposure of that epitope. Consistent with
a mechanism involving a mAb-mediated structural alteration of P1 on the cell surface, immunization with truncated P1 derivatives lacking segments that contribute to recognition by beneficial immunomodulatory mAbs resulted in an improvement in the ability of elicited serum Abs to inhibit bacterial adherence compared with immunization with the full-length protein. The Journal of Immunology, 2009, 183: 4628-4638.”
“Designing potent and subtype-selective ligands with therapeutic value requires knowledge about how endogenous ligands interact with their binding site. 4-Amino-3-hydroxybutanoic acid (GABOB) is an endogenous ligand found in the central nervous system
in mammals. It is a metabolic product of GABA, the major inhibitory neurotransmitter. Homology modeling of the GABA(C) rho(1) receptor revealed a potential H-bond interaction between the hydroxyl group of GABOB and threonine 244 (T244) located on loop C of the ligand binding site of the rho(1) subunit. Using site-directed buy Fedratinib mutagenesis, we examined the effect of mutating T244 on the efficacy and pharmacology of GABOB and various ligands. It was found that mutating T244 to amino acids that lacked a hydroxyl group in their side chains produced GABA insensitive receptors. Only by mutating rho(1)T244 to serine (rho(1)T244S) produced a GABA responsive receptor, albeit 39-fold less sensitive to GABA than rho(1)wild-type. We also observed changes in the activities of the GABA(C) receptor partial agonists, muscimol and imidazole-4-acetic acid (I4AA). At the concentrations we tested, the partial agonists antagonized GABA-induced currents at rho(1)T244S mutant receptors (Muscimol: rho(1)wild-type, EC50 = 1.4 mu M; rho(1)T244S, IC50 = 32.8 mu M. I4AA: rho(1)wild-type, EC50 = 8.6 mu M; rho(1)T244S, IC50 = 21.4 mu M). This indicates that T244 is predominantly involved in channel gating.