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Human macrophage inflammatory protein 3alpha: protein and peptide nuclear magnetic resonance solution structures, dimerization, dynamics, and anti-infective properties.

Abstract：

:Human macrophage inflammatory protein 3alpha (MIP-3alpha), also known as CCL20, is a 70-amino-acid chemokine which exclusively binds to chemokine receptor 6. In addition, the protein also has direct antimicrobial, antifungal, and antiviral activities. The solution structure of MIP-3alpha was solved by the use of two-dimensional homonuclear proton nuclear magnetic resonance (NMR). The structure reveals the characteristic chemokine fold, with three antiparallel beta strands followed by a C-terminal alpha helix. In contrast to the crystal structures of MIP-3alpha, the solution structure was found to be monomeric. Another difference between the NMR and crystal structures lies in the angle of the alpha helix with respect to the beta strands, which measure 69 and approximately 56.5 degrees in the two structures, respectively. NMR diffusion and pH titration studies revealed a distinct tendency for MIP-3alpha to form dimers at neutral pH and monomers at lower pH, dependent on the protonation state of His40. Molecular dynamics simulations of both the monomeric and the dimeric forms of MIP-3alpha supported the notion that the chemokine undergoes a change in helix angle upon dimerization and also highlighted the important hydrophobic and hydrogen bonding contacts made by His40 in the dimer interface. Moreover, a constrained N terminus and a smaller binding groove were observed in dimeric MIP-3alpha simulations, which could explain why monomeric MIP-3alpha may be more adept at receptor binding and activation. The solution structure of a synthetic peptide consisting of the last 20 residues of MIP-3alpha displayed a highly amphipathic alpha helix, reminiscent of various antimicrobial peptides. Antimicrobial assays with this peptide revealed strong and moderate bactericidal activities against Escherichia coli and Staphylococcus aureus, respectively. This confirms that the C-terminal alpha-helical region of MIP-3alpha plays a significant part in its broad anti-infective activity.

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

Chan DI,Hunter HN,Tack BF,Vogel HJ

doi

10.1128/AAC.00805-07

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

883-94

issue

eissn

0066-4804

issn

1098-6596

pii

AAC.00805-07

journal_volume

pub_type

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Human macrophage inflammatory protein 3alpha: protein and peptide nuclear magnetic resonance solution structures, dimerization, dynamics, and anti-infective properties.