A natural, single-residue substitution yields a less active peptaibiotic: the structure of bergofungin A at atomic...

Area of Science:

• Biochemistry
• Structural Biology
• Mycology

Background:

• Bergofungin is a peptide antibiotic produced by the fungus Emericellopsis donezkii.
• It belongs to the peptaibol subfamily 2, characterized by specific amino acid sequences.
• Understanding the structure-activity relationship of such natural products is crucial for drug discovery.

Purpose of the Study:

• To determine the crystal structure of bergofungin A.
• To compare its structure and folding with related peptaibols, such as samarosporin I.
• To investigate the impact of structural variations on antibiotic activity.

Main Methods:

• Crystallization of bergofungin A from methanol and water solutions.
• X-ray diffraction to determine and refine the crystal structure to 0.84 Å resolution.
• Agar diffusion tests to assess antibiotic activity.

Main Results:

• The crystal structure of bergofungin A, a 15-residue peptaibol, was elucidated.
• Bergofungin A exhibits 3₁₀-helical and α-helical secondary structures, similar to samarosporin I.
• An N-terminal valine residue in bergofungin A, replacing phenylalanine in samarosporin I, significantly reduces antibiotic activity.
• Bergofungin A crystals show a unique solvent channel near the N-terminus.

Conclusions:

• The N-terminal substitution in bergofungin A is responsible for its diminished antibiotic potency.
• Despite minor differences in hydrogen bonding and lattice packing, the overall molecular fold is conserved between bergofungin A and samarosporin I.
• Structural insights into bergofungin A provide a basis for understanding peptaibol function and designing novel antibiotics.