4ncj

Crystal Structure of Pyrococcus furiosis Rad50 R805E mutation with ADP Beryllium Flouride

spinqualitylabelsall models 4ncj, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ncj is a 4 chain structure with sequence from Pyrfu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ADP, BEF, MG Related: 4nch, 4nci, 4nck Gene: PF1167, rad50 (PYRFU) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [RAD50_PYRFU] Involved in DNA double-strand break repair (DSBR). The Rad50/Mre11 complex possesses single-strand endonuclease activity and ATP-dependent double-strand-specific 3'-5' exonuclease activity. Rad50 provides an ATP-dependent control of Mre11 by unwinding and/or repositioning DNA ends into the Mre11 active site.[HAMAP-Rule:MF_00449] Publication Abstract from PubMed The Mre11-Rad50 complex is highly conserved, yet the mechanisms by which Rad50 ATP-driven states regulate the sensing, processing and signaling of DNA double-strand breaks are largely unknown. Here we design structure-based mutations in Pyrococcus furiosus Rad50 to alter protein core plasticity and residues undergoing ATP-driven movements within the catalytic domains. With this strategy we identify Rad50 separation-of-function mutants that either promote or destabilize the ATP-bound state. Crystal structures, X-ray scattering, biochemical assays, and functional analyses of mutant PfRad50 complexes show that the ATP-induced 'closed' conformation promotes DNA end binding and end tethering, while hydrolysis-induced opening is essential for DNA resection. Reducing the stability of the ATP-bound state impairs DNA repair and Tel1 (ATM) checkpoint signaling in Schizosaccharomyces pombe, double-strand break resection in Saccharomyces cerevisiae, and ATM activation by human Mre11-Rad50-Nbs1 in vitro, supporting the generality of the P. furiosus Rad50 structure-based mutational analyses. These collective results suggest that ATP-dependent Rad50 conformations switch the Mre11-Rad50 complex between DNA tethering, ATM signaling, and 5' strand resection, revealing molecular mechanisms regulating responses to DNA double-strand breaks. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling.,Deshpande RA, Williams GJ, Limbo O, Williams RS, Kuhnlein J, Lee JH, Classen S, Guenther G, Russell P, Tainer JA, Paull TT EMBO J. 2014 Mar 3;33(5):482-500. doi: 10.1002/embj.201386100. Epub 2014 Feb 3. PMID:24493214 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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