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PDBsum entry 2eax
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Peptidoglycan-binding protein
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PDB id
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2eax
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References listed in PDB file
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Key reference
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Title
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Structural insights into the bactericidal mechanism of human peptidoglycan recognition proteins.
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Authors
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S.Cho,
Q.Wang,
C.P.Swaminathan,
D.Hesek,
M.Lee,
G.J.Boons,
S.Mobashery,
R.A.Mariuzza.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
8761-8766.
[DOI no: ]
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PubMed id
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Abstract
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Peptidoglycan recognition proteins (PGRPs) are highly conserved
pattern-recognition molecules of the innate immune system that bind bacterial
peptidoglycans (PGNs), which are polymers of alternating N-acetylglucosamine
(NAG) and N-acetylmuramic acid (NAM) cross-linked by short peptide stems. Human
PRGPs are bactericidal against pathogenic and nonpathogenic Gram-positive
bacteria, but not normal flora bacteria. Like certain glycopeptide antibiotics
(e.g., vancomycin), PGRPs kill bacteria by directly interacting with their cell
wall PGN, thereby interfering with PGN maturation. To better understand the
bactericidal mechanism of PGRPs, we determined the crystal structure of the
C-terminal PGN-binding domain of human PGRP-Ibeta in complex with
NAG-NAM-l-Ala-gamma-d-Glu-l-Lys-d-Ala-d-Ala, a synthetic glycopeptide comprising
a complete PGN repeat. This structure, in conjunction with the previously
reported NMR structure of a dimeric PGN fragment, permitted identification of
major conformational differences between free and PGRP-bound PGN with respect to
the relative orientation of saccharide and peptide moieties. These differences
provided structural insights into the bactericidal mechanism of human PGRPs. On
the basis of molecular modeling, we propose that these proteins disrupt cell
wall maturation not only by sterically encumbering access of biosynthetic
enzymes to the nascent PGN chains, but also by locking PGN into a conformation
that prevents formation of cross-links between peptide stems in the growing cell
wall.
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Figure 1.
Fig. 1. Structure of PGN and PGN derivatives. (A) Schematic
representation of Lys-type PGNs. Lys-type PGN peptides are
usually cross-linked through a peptide bridge composed of one to
five glycines. The fragment shown in red corresponds to GMPP.
(B) Chemical structure of GMPP. (C) GMPP[2]. (D) MPP (R^1, H)
and MPP-Dap (R^1, COOH).
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Figure 3.
Fig. 3. Structural comparison between PGRP-bound PGN
analogs in crystal structures and unbound GMPP[2] in solution.
(A) Conformational comparison of GMPP, MPP, TCT, and GMPP[2].
GMPP, MPP, and TCT are from crystal structures of complexes with
human PGRP-I  C, human PGRP-I  C (16),
and Drosophila PGRP-LE (27), respectively; GMPP[2] is from the
unliganded NMR structure (17). The structures are superposed
through the pyranose ring of NAM (for MPP, GMPP, and GMPP[2]) or
NAM(1,6-anhydro) (for TCT). (B) Superposition of unbound GMPP[2]
onto GMPP in the PGRP-I C–GMPP complex. GMPP
and GMPP[2] are shown in ball-and-stick representations, with
carbon atoms in yellow and green, respectively, nitrogen atoms
in blue, and oxygen atoms in red. Of the two GMPP units in
GMPP[2], the first unit, comprising the NAG[1]-NAM[1]
disaccharide, is superposed onto GMPP in the complex. The
peptide stem of GMPP[2] attached to NAM[1] is buried within
PGRP-I C and is shown in pale
green. (C) Alternative superposition of unliganded GMPP[2] onto
GMPP bound to PGRP-I C. In this case, the
second GMPP unit of GMPP[2], containing NAG[2]-NAM[2], is
superposed onto GMPP in the PGRP-I C–GMPP structure. The
peptide stem of GMPP[2] attached to NAM[2], shown in pale green,
is buried inside PGRP-I C. (D) Modeled PGRP-I
C–GMPP[2] structure.
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