title: Structural basis of recognition of pathogen-associated molecular patterns and inhibition of proinflammatory cytokines by camel peptidoglycan recognition protein.
abstract: Peptidoglycan recognition proteins (PGRPs) are involved in the recognition of pathogen-associated molecular patterns. The well known pathogen-associated molecular patterns include LPS from Gram-negative bacteria and lipoteichoic acid (LTA) from Gram-positive bacteria. In this work, the crystal structures of two complexes of the short form of camel PGRP (CPGRP-S) with LPS and LTA determined at 1.7- and 2.1-Å resolutions, respectively, are reported. Both compounds were held firmly inside the complex formed with four CPGRP-S molecules designated A, B, C, and D. The binding cleft is located at the interface of molecules C and D, which is extendable to the interface of molecules A and C. The interface of molecules A and B is tightly packed, whereas that of molecules B and D forms a wide channel. The hydrophilic moieties of these compounds occupy a common region, whereas hydrophobic chains interact with distinct regions in the binding site. The binding studies showed that CPGRP-S binds to LPS and LTA with affinities of 1.6 × 10(-9) and 2.4 × 10(-8) M, respectively. The flow cytometric studies showed that both LPS- and LTA-induced expression of the proinflammatory cytokines TNF-α and IL-6 was inhibited by CPGRP-S. The results of animal studies using mouse models indicated that both LPS- and LTA-induced mortality rates decreased drastically when CPGRP-S was administered. The recognition of both LPS and LTA, their high binding affinities for CPGRP-S, the significant decrease in the production of LPS- and LTA-induced TNF-α and IL-6, and the drastic reduction in the mortality rates in mice by CPGRP-S indicate its useful properties as an antibiotic agent.
authors: Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors: Pradeep
authors: P
authors: Sharma
authors: Divya
authors: D
authors: Dube
authors: Amar
authors: A
authors: Singh
authors: Biswajit
authors: B
authors: Mishra
authors: Nagendra
authors: N
authors: Singh
authors: Mau
authors: M
authors: Sinha
authors: Sharmistha
authors: S
authors: Dey
authors: Punit
authors: P
authors: Kaur
authors: Dipendra K
authors: DK
authors: Mitra
authors: Sujata
authors: S
authors: Sharma
authors: Tej P
authors: TP
authors: Singh
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002162:Camelus; D002352:Carrier Proteins / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D017434:Protein Structure, Tertiary; D013682:Teichoic Acids / Q000737:chemistry* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; C118897:peptidoglycan recognition protein; C009900:lipoteichoic acid