1zmh
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Crystal structure of human neutrophil peptide 2, HNP-2 (variant Gly16-> D-Ala)
OverviewOverview
Defensins are cationic antimicrobial mini-proteins that play important, roles in the innate immune defense against microbial infection. Six, invariant Cys residues in each defensin form three structurally, indispensable intramolecular disulfide bridges. The only other residue, invariant in all known mammalian defensins is a Gly. Structural studies, indicate that the invariant Gly residue is located in an atypical, classic-type beta-bulge with the backbone torsion angles (Phi, Psi), disallowed for L-amino acids but permissible for D-enantiomers. We, replaced the invariant Gly17 residue in human neutrophil alpha-defensin 2, (HNP2) by L-Ala or one of the D-amino acids Ala, Glu, Phe, Arg, Thr, Val, or Tyr. Although L-Ala17-HNP2 could not be folded, resulting in massive, aggregation, all of the D-amino acid-substituted analogs folded with high, efficiency. The high resolution x-ray crystal structures of dimeric, D-Ala17-HNP2 were determined in three different crystal forms, showing a, well preserved beta-bulge identical to those found in other defensins. The, seven D-analogs of HNP2 exhibited highly variable bactericidal activity, against Gram-positive and Gram-negative test strains, consistent with the, premise that interplay between charge and hydrophobicity dictates how, amphiphilic defensins kill. Further, the bactericidal activity of these, d-amino acid analogs of HNP2 correlated well with their ability to induce, leakage from large unilamellar vesicles, supporting membrane, permeabilization as the lethal event in microbial killing by HNP2. Our, findings identify a conformational prerequisite in the beta-bulge of, defensins essential for correct folding and native structure, thereby, explaining the molecular basis of the Gly-Xaa-Cys motif conserved in all, mammalian defensins.
About this StructureAbout this Structure
1ZMH is a Single protein structure of sequence from Homo sapiens with SO4, P6G and GOL as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Reconstruction of the conserved beta-bulge in mammalian defensins using D-amino acids., Xie C, Prahl A, Ericksen B, Wu Z, Zeng P, Li X, Lu WY, Lubkowski J, Lu W, J Biol Chem. 2005 Sep 23;280(38):32921-9. Epub 2005 May 13. PMID:15894545
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