This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The innate immune system constitutes the first line of defense against microorganisms by means of conserved pattern recognition receptors (PRRs) that bind unique products of microbial metabolism not produced by the host. Although much progress has been made towards identifying key receptors and understanding their role in host defense, far less is known about how these receptors recognize microbial ligands. Such studies have been severely hindered by the need to purify ligands from microbial sources, and a reliance on biological assays, rather than direct binding, to monitor recognition. Peptidoglycan recognition proteins (PGRPs) are a relatively new class of pattern recognition receptors that are highly conserved from insects to mammals. Although the importance of these proteins for immune surveillance has been established, their mode of action is not well understood. We have used a range of synthetic peptidoglycan (PGN) derivatives, combined with Surface Plasmon Resonance (SPR), to define the binding specificities of two human peptidogycan recognition proteins (PGRPs). We have demonstrated that these innate immune receptors distinguish between PGNs from different bacteria based on the composition of the PGN peptide stem. We have also been able to determine which structural elements of peptidodiglycan are important for binding for the two PGRPs. These binding profiles have been rationalized by using an X-ray crystal structure of PGRP-I? with a lysine containing muramyl tripeptide and sequence homology.
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