SNAP annotations: PDB entry 10mj

PDB-id

10mj; DSSR-derived features in text and JSON formats; DNAproDB

Class

transcription

Method

cryo-EM (3.3 Å)

Summary

Open mtb-ec: cryo-EM structure of mtb rnap elongation complex (substrate loading mimic) with an open active site (open tl and rh-fl)

Reference

Dhingra Y, Landick R, Campbell EA, Darst SA (2026): "RNA polymerase inhibitors reveal active-site motions essential for the nucleotide-addition cycle." Biorxiv. doi: 10.64898/2026.04.06.716786.

Abstract

The nucleotide-addition cycle (NAC) of multi-subunit DNA-dependent RNA polymerases (RNAPs) involves coordinated conformational changes in conserved active-site structural elements, including the trigger loop (TL). The TL is open (unfolded) in most RNAP structures but can close (fold) in substrate-bound (post- or pre-translocated) states of the RNAP, promoting catalysis. TL closure has been associated with closure of another conserved structural element, the Rim-Helices/F-loop (RH-FL), but the role of the RH-FL in the NAC is unclear. Antibiotic leads CBR9379 and AAP-SO ₂ inhibit the <i>Escherichia coli</i> and <i>Mycobacterium tuberculosis</i> RNAPs, respectively, by binding in a pocket formed by the bridge helix and RH-FL. The precise mechanism of action for these inhibitors is yet to be defined. We present cryo-electron microscopy structures showing that both compounds inhibit the RNAP NAC by preventing RH-FL closure, thereby allosterically destabilizing the closed TL. This work reveals a conserved mechanistic principle of RNAP catalysis across all domains of life and provides new insight for antibiotic design.