6CUX
Escherichia coli RpoB S531L mutant RNA polymerase holoenzyme in complex with Kanglemycin A
Summary for 6CUX
Entry DOI | 10.2210/pdb6cux/pdb |
Descriptor | DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (8 entities in total) |
Functional Keywords | bacterial rna polymerase, kanglemycin a, transcription inhibitor, transcription, transcription-transcription inhibitor complex, transcription-antibiotic complex, transcription/antibiotic |
Biological source | Escherichia coli (strain K12) More |
Total number of polymer chains | 12 |
Total formula weight | 921162.07 |
Authors | Molodtsov, V.,Murakami, K.S. (deposition date: 2018-03-26, release date: 2018-07-25, Last modification date: 2024-11-20) |
Primary citation | Mosaei, H.,Molodtsov, V.,Kepplinger, B.,Harbottle, J.,Moon, C.W.,Jeeves, R.E.,Ceccaroni, L.,Shin, Y.,Morton-Laing, S.,Marrs, E.C.L.,Wills, C.,Clegg, W.,Yuzenkova, Y.,Perry, J.D.,Bacon, J.,Errington, J.,Allenby, N.E.E.,Hall, M.J.,Murakami, K.S.,Zenkin, N. Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis. Mol. Cell, 72:263-274.e5, 2018 Cited by PubMed Abstract: Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered-compared with rifampicin-conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. PubMed: 30244835DOI: 10.1016/j.molcel.2018.08.028 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (4.104 Å) |
Structure validation
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