Last stop on the road to repair: structure of E. coli DNA ligase bound to nicked DNA-adenylate.
NAD(+)-dependent DNA ligases (LigA) are ubiquitous in bacteria and essential for growth. Their distinctive substrate specificity and domain organization vis-a-vis human ATP-dependent ligases make them outstanding targets for anti-infective drug discovery. We report here the 2.3 A crystal structure of Escherichia coli LigA bound to an adenylylated nick, which captures LigA in a state poised for strand closure and reveals the basis for nick recognition. LigA envelopes the DNA within a protein clamp. Large protein domain movements and remodeling of the active site orchestrate progression through the three chemical steps of the ligation reaction. The structure inspires a strategy for inhibitor design.
Nandakumar
Jayakrishnan
J
Molecular Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
Nair
Pravin A
PA
Shuman
Stewart
S
D000227:Adenine Nucleotides / Q000737:chemistry; D001483:Base Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D053904:DNA Breaks, Single-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013045:Species Specificity
D000227:Adenine Nucleotides; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C497118:LigA protein, E coli