The crystal structure of archaeal serine hydroxymethyltransferase reveals idiosyncratic features likely required to withstand high temperatures

Abstract Serine hydroxymethyltransferases (SHMTs) play an essential role in one-carbon unit metabolism and are employed in biomimetic reactions. We determined the crystal structure of free (apo) and PLP-bound (holo) SHMT from Methanocaldococcus jannaschii, the first from a hyperthermophile and from the archaea domain of life, at 2.83 and 3.0 Å resolution, respectively. Idiosyncratic features were observed that are likely to contribute to structure stabilization. At the dimer interface, the C-terminal region folds in a unique fashion with respect to SHMTs from eubacteria and eukarya. At the active site, the conserved cation-π interaction is substituted by an on-face hydrogen bond between residues occurring almost exclusively in hyperthermophilic archaea. This led us to propose the reduction of frustration of functional residues as an additional strategy of adaptation to high temperature. Both peculiar features may be exploited to design novel enzymes with improved stability for applications in biomimetic processes.