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Dependent DNA Ligase (dependent + dna_ligase)

Distribution by Scientific Domains
Chemistry100%

Selected Abstracts

NAD+ -Dependent DNA Ligase: A novel target waiting for the right inhibitor,

MEDICINAL RESEARCH REVIEWS, Issue 4 2008
Namrata Dwivedi
Abstract DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single stranded or double stranded breaks between adjacent 5, phosphoryl and 3, hydroxyl groups of DNA. These enzymes are important for survival because they are involved in major cellular processes like DNA replication/repair and recombination. DNA ligases can be classified into two groups on the basis of their cofactor specificities. NAD+ -dependent DNA ligases are present in bacteria, some entomopox viruses and mimi virus while ATP-dependent DNA ligases are ubiquitous. The former have recently been drawing a lot of attention as novel targets for antibiotics to overcome current drug resistance issues. Currently a diverse range of inhibitors have been identified. There are several issues to be addressed in the quest for optimized inhibitors of the enzyme. In the first part of the review we summarize current structural work on these enzymes. Subsequently we describe the currently available classes of inhibitors. We also address modalities to improve the specificity and potencies of new inhibitors identified using protein structure based rational approaches. In conclusion, NAD+ -dependent ligases show great promise and represent a novel drug target whose time has come. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 545,568, 2008 [source]

Structure of the adenylation domain of NAD+ -dependent DNA ligase from Staphylococcus aureus

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 11 2009
Seungil Han
DNA ligase catalyzes phosphodiester-bond formation between immediately adjacent 5,-phosphate and 3,-hydroxyl groups in double-stranded DNA and plays a central role in many cellular and biochemical processes, including DNA replication, repair and recombination. Bacterial NAD+ -dependent DNA ligases have been extensively characterized as potential antibacterial targets because of their essentiality and their structural distinction from human ATP-dependent DNA ligases. The high-resolution structure of the adenylation domain of Staphylococcus aureus NAD+ -dependent DNA ligase establishes the conserved domain architecture with other bacterial adenylation domains. Two apo crystal structures revealed that the active site possesses the preformed NAD+ -binding pocket and the `C2 tunnel' lined with hydrophobic residues: Leu80, Phe224, Leu287, Phe295 and Trp302. The C2 tunnel is unique to bacterial DNA ligases and the Leu80 side chain at the mouth of the tunnel points inside the tunnel and forms a narrow funnel in the S. aureus DNA ligase structure. Taken together with other DNA ligase structures, the S. aureus DNA ligase structure provides a basis for a more integrated understanding of substrate recognition and catalysis and will be also be of help in the development of small-molecule inhibitors. [source]

NAD+ -Dependent DNA Ligase: A novel target waiting for the right inhibitor,

MEDICINAL RESEARCH REVIEWS, Issue 4 2008
Namrata Dwivedi
Abstract DNA ligases (EC.6.5.1.1) are key enzymes that catalyze the formation of phosphodiester bonds at single stranded or double stranded breaks between adjacent 5, phosphoryl and 3, hydroxyl groups of DNA. These enzymes are important for survival because they are involved in major cellular processes like DNA replication/repair and recombination. DNA ligases can be classified into two groups on the basis of their cofactor specificities. NAD+ -dependent DNA ligases are present in bacteria, some entomopox viruses and mimi virus while ATP-dependent DNA ligases are ubiquitous. The former have recently been drawing a lot of attention as novel targets for antibiotics to overcome current drug resistance issues. Currently a diverse range of inhibitors have been identified. There are several issues to be addressed in the quest for optimized inhibitors of the enzyme. In the first part of the review we summarize current structural work on these enzymes. Subsequently we describe the currently available classes of inhibitors. We also address modalities to improve the specificity and potencies of new inhibitors identified using protein structure based rational approaches. In conclusion, NAD+ -dependent ligases show great promise and represent a novel drug target whose time has come. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 4, 545,568, 2008 [source]

Structure of the adenylation domain of NAD+ -dependent DNA ligase from Staphylococcus aureus

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 11 2009
Seungil Han
DNA ligase catalyzes phosphodiester-bond formation between immediately adjacent 5,-phosphate and 3,-hydroxyl groups in double-stranded DNA and plays a central role in many cellular and biochemical processes, including DNA replication, repair and recombination. Bacterial NAD+ -dependent DNA ligases have been extensively characterized as potential antibacterial targets because of their essentiality and their structural distinction from human ATP-dependent DNA ligases. The high-resolution structure of the adenylation domain of Staphylococcus aureus NAD+ -dependent DNA ligase establishes the conserved domain architecture with other bacterial adenylation domains. Two apo crystal structures revealed that the active site possesses the preformed NAD+ -binding pocket and the `C2 tunnel' lined with hydrophobic residues: Leu80, Phe224, Leu287, Phe295 and Trp302. The C2 tunnel is unique to bacterial DNA ligases and the Leu80 side chain at the mouth of the tunnel points inside the tunnel and forms a narrow funnel in the S. aureus DNA ligase structure. Taken together with other DNA ligase structures, the S. aureus DNA ligase structure provides a basis for a more integrated understanding of substrate recognition and catalysis and will be also be of help in the development of small-molecule inhibitors. [source]