X-ray Crystal Structure of Teicoplanin A₂-2 Bound to a Catalytic Peptide Sequence via the Carrier Protein Strategy

Abstract

We report the X-ray crystal structure of a site-selective peptide catalyst moiety and teicoplanin A2-2 complex. The expressed protein ligation technique was used to couple T4 lysozyme (T4L) and a synthetic peptide catalyst responsible for the selective phosphorylation of the N-acetylglucosamine sugar in a teicoplanin A2-2 derivative. The T4L-Pmh-dPro-Aib-dAla-dAla construct was crystallized in the presence of teicoplanin A2-2. The resulting 2.3 Å resolution protein–peptide–teicoplanin complex crystal structure revealed that the nucleophilic nitrogen of N-methylimidazole in the Pmh residue is in closer proximity (7.6 Å) to the N-acetylglucosamine than the two other sugar rings present in teicoplanin (9.3 and 20.3 Å, respectively). This molecular arrangement is consistent with the observed selectivity afforded by the peptide-based catalyst when it is applied to a site-selective phosphorylation reaction involving a teicoplanin A2-2 derivative.

Binding modes identification through molecular dynamic simulations: A case study with carnosine enantiomers and the Teicoplanin A2‐2‐based chiral stationary phase

“…The Maestro graphical interface of the Schrödinger Suite 2018‐4 (Schrödinger, New York, NY, 2018) was used. The 3D structure of the chiral selector Teicoplanin A2‐2 was retrieved from the Protein Data Bank (PDB code 4PJZ) [19] and checked for missing atoms, bonds, and stereochemistry correctness. Carnosine and Teicoplanin A2‐2 contain multiple ionizable groups, thus the MoKa 2.6.6 software [20,21] was used to correctly assign the predominant tautomeric and protomeric forms in the experimental conditions (4.5).…”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…122 Building on previously reported results in which appending a carrier-protein to the D Ala- D Ala-containing peptide 123 enabled more facile X-ray crystal structure determinations, complexation between 57 and teicoplanin was observed. As hypothesized, the Pmh-residue was oriented directly adjacent to the green sugar and the primary alcohol owing to the specificity of the teicoplanin-binding pocket for coordinating to D Ala- D Ala sequences.…”

Structure Diversification of Vancomycin through Peptide-Catalyzed, Site-Selective Lipidation: A Catalysis-Based Approach To Combat Glycopeptide-Resistant Pathogens

“…From earlier work, 15 we have compelling evidence that 8 binds to the ligand binding pocket of vancomycin through a series of hydrogen bonds with the backbone amides (Figure 3b). 55 However, it is unclear if the same sets of amide bonds are also playing a role in recruiting 6 and 7 . To probe this, we performed the acylation reactions with each catalyst in the presence of Boc-Leu- D Ala- D Ala-OH (1 equiv) as a competing ligand for the binding pocket (see Supporting Information).…”