The solution structure of the lantibiotic gallidermin.
The 21-peptide amide antibiotic gallidermin is a potential therapeutic against acne disease. It belongs to the class of polycyclic lanthionine and alpha,beta-didehydroamino acids containing polypeptides, which were named "lantibiotics." The structural gene of the recently elucidated lantibiotic gallidermin encodes a precursor peptide containing Ser, Thr, and Cys residues in the C-terminal prolantibiotic part, and an unusually hydrophilic leader peptide. The ribosomally synthesized pregallidermin is posttranslationally modified and processed to a complex peptide antibiotic with four sulfide rings and two unsaturated residues. The complete solution structure of gallidermin was determined in trifluoroethanol: water (95:5) and dimethylsulfoxide by two-dimensional 1H-nmr at 500 MHz, using a combination of double quantum filtered correlated spectroscopy, homonuclear Hartman-Hahn, and nuclear Overhauser enhancement spectroscopy experiments. Using a total number of 152 distance constraints from NOEs and 14 torsional constraints, derived from coupling constants, we obtained a screwlike solution structure of gallidermin. Restrained molecular dynamics simulations yielded a set of five converging structures with an atomic rms difference of 1.7 A for the backbone atoms, not dependent on the starting structure. The spatial structure model is in excellent agreement with the amphiphilic and channel-forming properties of gallidermin on membranes and its tryptic cleavage at the exposed site between residues 13 and 14.
Institut für Organische Chemie, Universität Tübingen, Federal Republic of Germany.
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Freund
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D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001430:Bacteriocins; D002942:Circular Dichroism; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010455:Peptides; D010456:Peptides, Cyclic / Q000737:chemistry; D012996:Solutions; D013696:Temperature
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D010455:Peptides; D010456:Peptides, Cyclic; D012996:Solutions; C057656:gallidermin