4ZH2

Crystal structure of Escherichia coli RNA polymerase in complex with CBR703

Summary for 4ZH2

• Entry DOI: 10.2210/pdb4zh2/pdb
• Related: 4ZH3 4ZH4
• 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: rna polymerase, inhibitor, transcription, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli; More
• Total number of polymer chains: 12
• Total formula weight: 923999.81

Authors

Feng, Y.,Ebright, R.H. (deposition date: 2015-04-24, release date: 2015-08-05, Last modification date: 2023-09-27)

Primary citation

Feng, Y.,Degen, D.,Wang, X.,Gigliotti, M.,Liu, S.,Zhang, Y.,Das, D.,Michalchuk, T.,Ebright, Y.W.,Talaue, M.,Connell, N.,Ebright, R.H.
Structural Basis of Transcription Inhibition by CBR Hydroxamidines and CBR Pyrazoles.
Structure, 23:1470-1481, 2015

PubMed Abstract: CBR hydroxamidines are small-molecule inhibitors of bacterial RNA polymerase (RNAP) discovered through high-throughput screening of synthetic-compound libraries. CBR pyrazoles are structurally related RNAP inhibitors discovered through scaffold hopping from CBR hydroxamidines. CBR hydroxamidines and pyrazoles selectively inhibit Gram-negative bacterial RNAP and exhibit selective antibacterial activity against Gram-negative bacteria. Here, we report crystal structures of the prototype CBR hydroxamidine, CBR703, and a CBR pyrazole in complex with E. coli RNAP holoenzyme. In addition, we define the full resistance determinant for CBR703, show that the binding site and resistance determinant for CBR703 do not overlap the binding sites and resistance determinants of other characterized RNAP inhibitors, show that CBR703 exhibits no or minimal cross-resistance with other characterized RNAP inhibitors, and show that co-administration of CBR703 with other RNAP inhibitors results in additive antibacterial activities. The results set the stage for structure-based optimization of CBR inhibitors as antibacterial drugs.

PubMed: 26190576
DOI: 10.1016/j.str.2015.06.009

Experimental method

X-RAY DIFFRACTION (4.204 Å)