Vancomycin resistance: structure of D-alanine:D-alanine ligase at 2.3 A resolution.
The molecular structure of the D-alanine:D-alanine ligase of the ddlB gene of Escherichia coli, co-crystallized with an S,R-methylphosphinate and adenosine triphosphate, was determined by x-ray diffraction to a resolution of 2.3 angstroms. A catalytic mechanism for the ligation of two D-alanine substrates is proposed in which a helix dipole and a hydrogen-bonded triad of tyrosine, serine, and glutamic acid assist binding and deprotonation steps. From sequence comparison, it is proposed that a different triad exists in a recently discovered D-alanine:D-lactate ligase (VanA) present in vancomycin-resistant enterococci. A molecular mechanism for the altered specificity of VanA is suggested.
Fan
C
C
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269-3125.
Moews
P C
PC
Walsh
C T
CT
Knox
J R
JR
D000244:Adenosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D019729:Carbon-Oxygen Ligases; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D006860:Hydrogen Bonding; D008025:Ligases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010453:Peptide Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014640:Vancomycin / Q000494:pharmacology*
D001426:Bacterial Proteins; D004151:Dipeptides; C071437:VanA ligase, Bacteria; C002956:alanylalanine; D000244:Adenosine Diphosphate; D014640:Vancomycin; D008025:Ligases; D019729:Carbon-Oxygen Ligases; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase