1 research outputs found
A Carrier Protein Strategy Yields the Structure of Dalbavancin
Many large natural product antibiotics act by specifically
binding
and sequestering target molecules found on bacterial cells. We have
developed a new strategy to expedite the structural analysis of such
antibiotic–target complexes, in which we covalently link the
target molecules to carrier proteins, and then crystallize the entire
carrier–target–antibiotic complex. Using native chemical
ligation, we have linked the Lys-d-Ala-d-Ala binding
epitope for glycopeptide antibiotics to three different carrier proteins.
We show that recognition of this peptide by multiple antibiotics is
not compromised by the presence of the carrier protein partner, and
use this approach to determine the first-ever crystal structure for
the new therapeutic dalbavancin. We also report the first crystal
structure of an asymmetric ristocetin antibiotic dimer, as well as
the structure of vancomycin bound to a carrier–target fusion.
The dalbavancin structure reveals an antibiotic molecule that has
closed around its binding partner; it also suggests mechanisms by
which the drug can enhance its half-life by binding to serum proteins,
and be targeted to bacterial membranes. Notably, the carrier protein
approach is not limited to peptide ligands such as Lys-d-Ala-d-Ala, but is applicable to a diverse range of targets. This
strategy is likely to yield structural insights that accelerate new
therapeutic development