Molecular Basis of Ligand Recognition by Mammalian Peptidoglycan Recognition Protein

Abstract

Short peptidoglycan recognition protein (PGRP-S) is a member of the innate immune system which provides the first line of defense to hosts against invading microbes. PGRP-S recognizes conserved motifs called pathogen associated molecular patterns (PAMPs) present in microorganisms but absent in host. We have determined the structure of camel peptidoglycan recognition protein (CPGRP-S) with various PAMPs like peptidoglycans, lipopolysaccharide, lipoteichoic acid, mycolic acid and five different fatty acids. The native structure revealed the presence of four crystallographically independent molecules A, B, C and D in the asymmetric unit. The buried surface area calculations indicated two stable contact regions, A-B and C-D which corresponded to opposite faces of the protein molecule resulting in the formation of a linear chain with alternating A-B and C-D contacts. This leads to the formation of multiple subsites contributed by molecules A, C, and D and a supporting diffusion channel formed by B and D molecules. The co-complexed structures indicated that the glycan moieties which contain PAMPs bind at C-D interface (PAMP-binding site) whereas the fatty acids occupy the cleft formed at A-B interface demonstrating that the binding sites for glycans and fatty acids are independent of each other. Similarly, the binary complex with the muramyl dipeptide and ternary complex with N-acetyl-D-glucosamine and beta-maltose revealed that these are accommodated in different sub-regions of the PAMP-binding site. This indicates that the PAMP-binding site is capable of accepting different kinds of PAMPs exhibiting varying specificities. It thus appears that the mode of binding of CPGRP-S essentially involves the interactions with the bacterial cell wall surface molecular patterns rather than cell membranes leading to the sequestration of the bacteria. Hence, CPGRP-S may be a protein antibiotic which may not suffer from bacterial resistance.