6EXV

Structure of mammalian RNA polymerase II elongation complex inhibited by Alpha-amanitin

Summary for 6EXV

• Entry DOI: 10.2210/pdb6exv/pdb
• EMDB information: 3981
• Related PRD ID: PRD_000201
• Descriptor: DNA-DIRECTED RNA POLYMERASE II SUBUNIT RPB1, DNA-directed RNA polymerases I, II, and III subunit RPABC5, DNA-DIRECTED RNA POLYMERASES I, II, AND III SUBUNIT RPABC4, ... (18 entities in total)
• Functional Keywords: inhibitor, elongation, active site, transcription
• Biological source: Sus scrofa (Pig); More
• Total number of polymer chains: 16
• Total formula weight: 550928.31

Authors

Liu, X.,Farnung, L.,Wigge, C.,Cramer, P. (deposition date: 2017-11-09, release date: 2018-03-21, Last modification date: 2025-04-09)

Primary citation

Liu, X.,Farnung, L.,Wigge, C.,Cramer, P.
Cryo-EM structure of a mammalian RNA polymerase II elongation complex inhibited by alpha-amanitin.
J. Biol. Chem., 293:7189-7194, 2018

PubMed Abstract: RNA polymerase II (Pol II) is the central enzyme that transcribes eukaryotic protein-coding genes to produce mRNA. The mushroom toxin α-amanitin binds Pol II and inhibits transcription at the step of RNA chain elongation. Pol II from yeast binds α-amanitin with micromolar affinity, whereas metazoan Pol II enzymes exhibit nanomolar affinities. Here, we present the high-resolution cryo-EM structure of α-amanitin bound to and inhibited by its natural target, the mammalian Pol II elongation complex. The structure revealed that the toxin is located in a pocket previously identified in yeast Pol II but forms additional contacts with metazoan-specific residues, which explains why its affinity to mammalian Pol II is ∼3000 times higher than for yeast Pol II. Our work provides the structural basis for the inhibition of mammalian Pol II by the natural toxin α-amanitin and highlights that cryo-EM is well suited to studying interactions of a small molecule with its macromolecular target.

PubMed: 29550768
DOI: 10.1074/jbc.RA118.002545

Experimental method

ELECTRON MICROSCOPY (3.6 Å)