5agu | pdb_00005agu

The sliding clamp of Mycobacterium tuberculosis in complex with a natural product.

spinqualitylabelsall models 5agu, resolution 2.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5agu is a 4 chain structure with sequence from Mycobacterium tuberculosis H37Rv and Streptomyces muensis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.173Å Ligands: ACE, BU3, MLU, MP8, MVA, NZC, TRS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DPO3B_MYCTU DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. This DNA polymerase also exhibits 3' to 5' exonuclease activity. The beta chain is required for initiation of replication once it is clamped onto DNA, it slides freely (bidirectional and ATP-independent) along duplex DNA (By similarity). Publication Abstract from PubMed The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification. Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.,Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, Zaburannyi N, Herrmann J, Wenzel SC, Konig C, Ammerman NC, Barrio MB, Borchers K, Bordon-Pallier F, Bronstrup M, Courtemanche G, Gerlitz M, Geslin M, Hammann P, Heinz DW, Hoffmann H, Klieber S, Kohlmann M, Kurz M, Lair C, Matter H, Nuermberger E, Tyagi S, Fraisse L, Grosset JH, Lagrange S, Muller R Science. 2015 Jun 5;348(6239):1106-12. doi: 10.1126/science.aaa4690. PMID:26045430 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DNA polymerase 3D structures

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