Today my laboratory is thrilled to announce a major breakthrough in the fight against the common cold and other diseases like hand,foot, and mouth disease acute flaccid myelitis caused by picornaviruses. We present the first structure of picornaviral 2C, bound to ssRNA (1/n)
We found that this AAA+ 2C holoenzyme more resembles a protein translocase rather than a helicase, which was unexpected but then again, this is the first ever RNA AAA+ complex ever seen. (7/n)
Uniquely, it uses carbonyl atoms from the backbone of one of its pores to confer specific RNA selectivity hydrogen bonding at the 2′-OH. This reminded us so much of how ion channels confer selectivity to substrate by also using backbone carbonyls in a pore (6/n)
Much work has been devoted to developing inhibitors and therapeutics targeting 2C, specifically in enteroviruses that have caused several outbreaks all around the world recently, but no structure of 2C bound to its substrate RNA has ever been solved until now (4/n)
In our work, we characterize the unique and specific binding modality of this AAA+ protein bound to RNA. No AAA+ protein has ever been seen to bind to ssRNA, so this work also provides the biophysical principles of how this protein specifically binds RNA (5/n)
Picornaviruses cause likely upwards of 8 billion infections per year and pose a severe disease and death toll on mankind. Beyond that, picornaviruses can also infect cattle and overall pose a severe economic burden to the glove as well (2/n)
2C is one of the most highly conserved proteins in all of these different viruses (e.g. enteroviruses, rhinoviruses, hepatitis A virus, poliovirus etc) and has been known to bind to RNA as a critical complex in viral replication (3/n)
Lastly, we used structural phylogenetics to search through metagenomic databases and found that there are many 2C-like proteins in many different viral families outside of picornaviruses, suggesting that our work here could have even broader ramifications than we thought (8/n)
This work could not have been possible without the amazing support of our collaborators in Dr. Trevor Sweeney’s laboratory and of course the amazing people (Richard, Louie and Maeva) that accelerated this work so much (9/n)