6bkf

Lysyl-adenylate form of human LigIV catalytic domain with bound DNA substrate in open conformation

spinqualitylabelsall models 6bkf, resolution 3.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bkf is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.25Å Ligands: AMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DNLI4_HUMAN Defects in LIG4 are the cause of LIG4 syndrome (LIG4S) [MIM:606593. This disease is characterized by immunodeficiency and developmental and growth delay. Patients display unusual facial features, microcephaly, growth and/or developmental delay, pancytopenia, and various skin abnormalities. Defects in LIG4 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID) [MIM:602450. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity. Function DNLI4_HUMAN Efficiently joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. Publication Abstract from PubMed DNA ligase IV (LigIV) performs the final DNA nick-sealing step of classical nonhomologous end-joining, which is critical for immunoglobulin gene maturation and efficient repair of genotoxic DNA double-strand breaks. Hypomorphic LigIV mutations cause extreme radiation sensitivity and immunodeficiency in humans. To better understand the unique features of LigIV function, here we report the crystal structure of the catalytic core of human LigIV in complex with a nicked nucleic acid substrate in two distinct states-an open lysyl-AMP intermediate, and a closed DNA-adenylate form. Results from structural and mutagenesis experiments unveil a dynamic LigIV DNA encirclement mechanism characterized by extensive interdomain interactions and active site phosphoanhydride coordination, all of which are required for efficient DNA nick sealing. These studies provide a scaffold for defining impacts of LigIV catalytic core mutations and deficiencies in human LIG4 syndrome. Structures of DNA-bound human ligase IV catalytic core reveal insights into substrate binding and catalysis.,Kaminski AM, Tumbale PP, Schellenberg MJ, Williams RS, Williams JG, Kunkel TA, Pedersen LC, Bebenek K Nat Commun. 2018 Jul 6;9(1):2642. doi: 10.1038/s41467-018-05024-8. PMID:29980672 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA ligase 3D structures

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