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. Peptidoglycan recognition proteins (PGRPs) are pattern recognition molecules of the innate immune system that bind and, in certain cases, hydrolyze peptidoglycans (PGNs) of bacterial cell walls (1). They are highly conserved from insects to mammals. PGRPs bind PGNs with high affinity and are important contributors to host defense against bacterial infections. Insects PGRPs, of which there are at least 19, are involved in activating signaling pathways that induce expression of anti-microbial peptides. By contrast, mammalian PGRPs, of which there are four, do not act through host signaling pathways, but are directly bactericidal against both Gram-positive and -negative bacteria (1). Indeed, these PGRPs are a new class of bactericidal proteins that have a different structure and mechanism of action than currently known mammalian antimicrobial peptides. Mammalian PGRP-L is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes PGN. Very recently, it was found that PGRP-L also has a proinflammatory function, unrelated to its amidase activity (2). We previously published structures of human PGRP-Ialpha and -Ibeta in complex with PGN fragments, and have proposed a mechanism for their bactericidal activity (3,4). We now plan to extend our work to PGRP-L, which contains a large N-terminal domain with no sequence homology to other known proteins, and whose structure remains to be established. The PGRP-L structure will provide insights into how three different types of pattern recognition molecules (PGRPs, Nod2 and TLR4) play interdependent roles in inflammatory responses to bacterial pathogens. Recently, We obtained a few small crystals which are too small (~50um) for data collection with our in-house detector. They diffract to a maximum resolution of 7 ? with unit cell dimensions of
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