5AH2

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

Summary for 5AH2

• Entry DOI: 10.2210/pdb5ah2/pdb
• Related: 5AGU 5AGV 5AH4
• Related PRD ID: PRD_002311
• Descriptor: DNA POLYMERASE III SUBUNIT BETA, GRISELIMYCIN, SODIUM ION, ... (4 entities in total)
• Functional Keywords: transferase-antibiotic complex, dnan, dna polymerase, tuberculosis, transferase/antibiotic
• Biological source: MYCOBACTERIUM SMEGMATIS; More
• Total number of polymer chains: 8
• Total formula weight: 171276.10

Authors

Lukat, P.,Kling, A.,Heinz, D.W.,Mueller, R. (deposition date: 2015-02-04, release date: 2015-06-03, Last modification date: 2024-01-10)

Primary citation

Kling, A.,Lukat, P.,Almeida, D.V.,Bauer, A.,Fontaine, E.,Sordello, S.,Zaburannyi, N.,Herrmann, J.,Wenzel, S.C.,Koenig, C.,Ammermann, N.C.,Barrio, M.B.,Borchers, K.,Bordon-Pallier, F.,Broenstrup, M.,Courtemanche, G.,Gerlitz, M.,Geslin, M.,Hammann, P.,Heinz, D.W.,Hoffmann, H.,Klieber, S.,Kohlmann, M.,Kurz, M.,Lair, C.,Matter, H.,Nuermberger, E.,Tyagi, S.,Fraisse, L.,Grosset, J.H.,Lagrange, S.,Mueller, R.
Antibiotics. Targeting Dnan for Tuberculosis Therapy Using Novel Griselimycins.
Science, 348:1106-, 2015

PubMed Abstract: 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.

PubMed: 26045430
DOI: 10.1126/SCIENCE.AAA4690

Experimental method

X-RAY DIFFRACTION (2.129 Å)