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PDBsum entry 2pms
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Metal transport, hydrolase
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PDB id
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2pms
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References listed in PDB file
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Key reference
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Title
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Structure of a complex of human lactoferrin n-Lobe with pneumococcal surface protein a provides insight into microbial defense mechanism.
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Authors
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O.Senkovich,
W.J.Cook,
S.Mirza,
S.K.Hollingshead,
I.I.Protasevich,
D.E.Briles,
D.Chattopadhyay.
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Ref.
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J Mol Biol, 2007,
370,
701-713.
[DOI no: ]
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PubMed id
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Abstract
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Human lactoferrin, a component of the innate immune system, kills a wide variety
of microorganisms including the Gram positive bacteria Streptococcus pneumoniae.
Pneumococcal surface protein A (PspA) efficiently inhibits this bactericidal
action. The crystal structure of a complex of the lactoferrin-binding domain of
PspA with the N-lobe of human lactoferrin reveals direct and specific
interactions between the negatively charged surface of PspA helices and the
highly cationic lactoferricin moiety of lactoferrin. Binding of PspA blocks
surface accessibility of this bactericidal peptide preventing it from
penetrating the bacterial membrane. Results of site-directed mutagenesis, in
vitro protein binding assays and isothermal titration calorimetry measurements
corroborate that the specific electrostatic interactions observed in the crystal
structure represent major associations between PspA and lactoferrin. The
structure provides a snapshot of the protective mechanism utilized by pathogens
against the host's first line of defense. PspA represents a major virulence
factor and a promising vaccine candidate. Insights from the structure of the
complex have implications for designing therapeutic strategies for treatment and
prevention of pneumococcal diseases that remain a major public health problem
worldwide.
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Figure 1.
Figure 1. Structure of the PspA[2]:NLF complex. (a)
Asymmetric unit content. LF N-lobes are shown in green (Lfcn
peptide is colored blue), PspA[2] molecules in red. One Fe ion
(orange) is bound to each NLF. The coordinating carbonate ligand
is shown in sticks. One Zn ion (cyan) is bound at the N-terminal
end of each PspA[2] molecule. The N-acetylglucosamine molecule
is labeled NAG. (b) PspA[2] structure. Residue numbering for
PspA[2] helices are shown.
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Figure 7.
Figure 7. (a) Superposition of the NMR structure of intact
LfcnH peptide (yellow) on the lactoferricin domain (residues
3–49) of the NLF (green) from the PspA[2]:NLF complex. The
conformation of the first helix of the Lfcn domain is very
similar in both structures although the β-sheet is unfolded in
the LfcnH peptide. (b) Residues in the first helix of NLF
(green) that interact with various residues of PspA[2] (salmon)
are shown in stick model. This helix of NLF provides many
contacts with PspA. The corresponding section of LfcnH peptide
is shown in yellow.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
370,
701-713)
copyright 2007.
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