9i91 | pdb_00009i91
Ku from Mycobacterium tuberculosis bound to DNA
Structural highlights
FunctionKU_MYCTU With LigD forms a non-homologous end joining (NHEJ) repair enzyme. Binds linear dsDNA with 5'- and 3'-overhangs but not closed circular dsDNA nor ssDNA. One dimer binds for every 30 bp. Recruits and stimulates the ligase activity of LigD but not of T4 ligase or a human ligase complex (LIG4/XRCC4). Attenuates the 3'- to 5'-exonuclease activity of LigD. Stimulates the template-directed addition of dNTPs by LigD on 5'-overhangs and nuclease activity on 3'-overhangs.[1] [2] [3] [4] Publication Abstract from PubMedMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is estimated to infect nearly one-quarter of the global population. A key factor in its resilience and persistence is its robust DNA repair capacity. Non-homologous end joining (NHEJ) is the primary pathway for repairing DNA double-strand breaks (DSBs) in many organisms, including Mtb, where it is mediated by the Ku protein and the multifunctional LigD enzyme. In this study, we demonstrate that Ku is essential for mycobacterial survival under DNA-damaging conditions. Using cryogenic electron microscopy (cryo-EM), we solved high-resolution structures of both the apo and DNA-bound forms of the Ku-Mtb homodimer. Our structural and biophysical analyses reveal that Ku forms an extended proteo-filament upon binding DNA. We identify critical residues involved in filament formation and DNA synapsis and show that their mutation severely impairs bacterial viability. Furthermore, we propose a model in which the C-terminus of Ku regulates DNA binding and loading and facilitates subsequent recruitment of LigD. These findings provide unique insights into bacterial DNA repair and guide future therapeutics. Oligomerisation of Ku from Mycobacterium tuberculosis promotes DNA synapsis.,Zahid S, Baconnais S, Smith H, Atwal S, Bates L, Read H, Chadda A, Morati F, Bedwell T, Stender EGP, Walter J, Hardwick SW, Westerlund F, Galburt E, Le Cam E, Pyne A, Mukamolova GV, Chaplin AK Nat Commun. 2025 Nov 26;16(1):10568. doi: 10.1038/s41467-025-65609-y. PMID:41298423[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
