Structural basis for peptidoglycan binding by peptidoglycan recognition proteins.
Peptidoglycan (PGN) recognition proteins (PGRPs) are pattern-recognition receptors of the innate immune system that bind and, in some cases, hydrolyze bacterial PGNs. We determined the crystal structure, at 2.30-A resolution, of the C-terminal PGN-binding domain of human PGRP-Ialpha in complex with a muramyl tripeptide representing the core of lysine-type PGNs from Gram-positive bacteria. The peptide stem of the ligand is buried at the deep end of a long binding groove, with N-acetylmuramic acid situated in the middle of the groove, whose shallow end can accommodate a linked N-acetylglucosamine. Although most interactions are with the peptide, the glycan moiety also seems to be essential for specific recognition by PGRPs. Conservation of key PGN-contacting residues shows that all PGRPs employ this basic PGN-binding mode. The structure pinpoints variable residues that likely mediate discrimination between lysine- and diaminopimelic acid-type PGNs. We also propose a mechanism for PGN hydrolysis by Zn(2+)-containing PGRPs.
Guan
Rongjin
R
Center for Advanced Research in Biotechnology, W. M. Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, MD 20850, USA.
Roychowdhury
Abhijit
A
Ember
Brian
B
Kumar
Sanjay
S
Boons
Geert-Jan
GJ
Mariuzza
Roy A
RA
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D017124:Conserved Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D003960:Diaminopimelic Acid; D006094:Gram-Positive Bacteria / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008239:Lysine; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
D001426:Bacterial Proteins; D002352:Carrier Proteins; D010457:Peptidoglycan; C118897:peptidoglycan recognition protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D003960:Diaminopimelic Acid; C035104:muramylNAc-Ala-isoGln-Lys-tripeptide; D008239:Lysine