3D3H

Crystal structure of a complex of the peptidoglycan glycosyltransferase domain from Aquifex aeolicus and neryl moenomycin A

Summary for 3D3H

• Entry DOI: 10.2210/pdb3d3h/pdb
• Related: 2OQO
• Descriptor: Penicillin-insensitive transglycosylase, (2R)-3-{[(S)-{[(2R,3R,4R,5S,6S)-3-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2R,3R,4S,5R,6S)-6-carbamoyl-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]oxy}-4-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-hydroxy-6-({[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)tetrahydro-2H-pyran-2-yl]oxy}-6-carbamoyl-4-(carbamoyloxy)-5-hydroxy-5-methyltetrahydro-2H-pyran-2-yl]oxy}(hydroxy)phosphoryl]oxy}-2-{[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]oxy}propanoic acid (3 entities in total)
• Functional Keywords: peptidoglycan glycosyltransferase, cell wall biosynthesis, antibiotics, penicillin-binding protein, transglycosylase, moenomycin, antibiotic resistance, cell shape, cell wall biogenesis/degradation, hydrolase, inner membrane, membrane, multifunctional enzyme, peptidoglycan synthesis, signal-anchor, transmembrane, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Aquifex aeolicus
• Cellular location: Cell inner membrane; Single-pass type II membrane protein (By similarity): O66874
• Total number of polymer chains: 1
• Total formula weight: 24194.58

Authors

Yuan, Y.,Sliz, P.,Walker, S. (deposition date: 2008-05-11, release date: 2008-07-22, Last modification date: 2023-08-30)

Primary citation

Yuan, Y.,Fuse, S.,Ostash, B.,Sliz, P.,Kahne, D.,Walker, S.
Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.
Acs Chem.Biol., 3:429-436, 2008

PubMed Abstract: Peptidoglycan glycosyltransferases (PGTs), enzymes that catalyze the formation of the glycan chains of the bacterial cell wall, have tremendous potential as antibiotic targets. The moenomycins, a potent family of natural product antibiotics, are the only known active site inhibitors of the PGTs and serve as blueprints for the structure-based design of new antibacterials. A 2.8 A structure of a Staphylococcus aureus PGT with moenomycin A bound in the active site appeared recently, potentially providing insight into substrate binding; however, the protein-ligand contacts were not analyzed in detail and the implications of the structure for inhibitor design were not addressed. We report here the 2.3 A structure of a complex of neryl-moenomycin A bound to the PGT domain of Aquifex aeolicus PBP1A. The structure allows us to examine protein-ligand contacts in detail and implies that six conserved active site residues contact the centrally located F-ring phosphoglycerate portion of neryl-moenomycin A. A mutational analysis shows that all six residues play important roles in enzymatic activity. We suggest that small scaffolds that maintain these key contacts will serve as effective PGT inhibitors. To test this hypothesis, we have prepared, via heterologous expression of a subset of moenomycin biosynthetic genes, a novel moenomycin intermediate that maintains these six contacts but does not contain the putative minimal pharmacophore. This compound has comparable biological activity to the previously proposed minimal pharmacophore. The results reported here may facilitate the design of antibiotics targeted against peptidoglycan glycosyltransferases.

PubMed: 18642800
DOI: 10.1021/cb800078a

Experimental method

X-RAY DIFFRACTION (2.31 Å)