The RNA world hypothesis posits that RNA self-replication played a foundational role at the origin of life. To explore this hypothesis, researchers have used selection methods to discover RNA catalysts (ribozymes) with polymerase activity. Some such polymerase ribozymes can replicate parts of their own sequence but little about their three-dimensional structures was known. Using single-particle cryogenic electron microscopy (cryo-EM) and high-throughput mutation analysis, McRae et al (PNAS, 2024, 121 (3) e2313332121) obtained the structure of a triplet polymerase ribozyme (TPR) apoenzyme and map its functional landscape. The cryo-EM structure at 5-Å resolution reveals the TPR as an RNA heterodimer comprising a catalytic subunit and a noncatalytic, auxiliary subunit, resembling the shape of a left hand with thumb and fingers at a 70° angle. The two subunits are connected by two distinct kissing-loop (KL) interactions that are essential for polymerase function. Data suggest a model for templated RNA synthesis by the TPR holoenzyme, whereby heterodimer formation and KL interactions preorganize the TPR for optimal primer–template duplex binding, triplet substrate discrimination, and templated RNA synthesis. Here you can see the cryoEM structure of the heterodimeric triplet polymerase ribozyme (PDB code: 8T2P)

#molecularart ... #ribozyme ... #polymerase ... #selfpolymerizing ... #evolution ... #rnaworld ... #life ... #cryoem

Structure rendered with @proteinimaging and depicted with @corelphotopaint