4KN7

X-ray crystal structure of the Escherichia coli RNA polymerase in complex with Benzoxazinorifamycin-2c

Summary for 4KN7

• Entry DOI: 10.2210/pdb4kn7/pdb
• Related: 4KMU 4KN4
• 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: transcription, dna, rna, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Escherichia coli; More
• Total number of polymer chains: 12
• Total formula weight: 922194.23

Authors

Murakami, K.S. (deposition date: 2013-05-08, release date: 2013-05-22, Last modification date: 2023-09-20)

Primary citation

Molodtsov, V.,Nawarathne, I.N.,Scharf, N.T.,Kirchhoff, P.D.,Showalter, H.D.,Garcia, G.A.,Murakami, K.S.
X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins.
J.Med.Chem., 56:4758-4763, 2013

PubMed Abstract: Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3'-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3'-tail changes the σ region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential.

PubMed: 23679862
DOI: 10.1021/jm4004889

Experimental method

X-RAY DIFFRACTION (3.686 Å)