SNAP output for PDB entry 5uh6 [SNAP web server]

PDB-id

5uh6; SNAP-derived features in text and JSON formats; DNAproDB

Class

transcription-DNA-RNA-antibiotic

Method

X-ray (3.837 Å)

Summary

Crystal structure of mycobacterium tuberculosis transcription initiation complex containing 2ntrna in complex with rifampin

Reference

Lin W, Mandal S, Degen D, Liu Y, Ebright YW, Li S, Feng Y, Zhang Y, Mandal S, Jiang Y, Liu S, Gigliotti M, Talaue M, Connell N, Das K, Arnold E, Ebright RH (2017): "Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition." Mol. Cell, 66, 169-179.e8. doi: 10.1016/j.molcel.2017.03.001.

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug rifampin (Rif). We report crystal structures of Mtb RNAP, alone and in complex with Rif, at 3.8-4.4 Å resolution. The results identify an Mtb-specific structural module of Mtb RNAP and establish that Rif functions by a steric-occlusion mechanism that prevents extension of RNA. We also report non-Rif-related compounds-Nα-aroyl-N-aryl-phenylalaninamides (AAPs)-that potently and selectively inhibit Mtb RNAP and Mtb growth, and we report crystal structures of Mtb RNAP in complex with AAPs. AAPs bind to a different site on Mtb RNAP than Rif, exhibit no cross-resistance with Rif, function additively when co-administered with Rif, and suppress resistance emergence when co-administered with Rif.