Glycosyltransferases: Capturing catalytic states and conformational gating.
TL;DR
Together, these studies show how transient catalytic states, loop closure, acceptor distortion, and atypical catalytic strategies control reaction trajectory, substrate selectivity, and processivity, while exposing opportunities for inhibition.
Abstract
Glycosyltransferases (GTs) install and remodel glycans that regulate protein function and shape extracellular matrices and microbial envelopes. Recent high-resolution structures, enabled by cryo-EM and X-ray crystallography, and increasingly complemented by AI-assisted modeling, now capture GTs in mechanistically informative states, including donor-acceptor complexes, gated conformations, and membrane polymerases engaged with nascent chains. In parallel, molecular simulations, including MD and QM/MM methodologies, are being used in selected GTs to map free-energy landscapes and resolve how active-site electrostatics and conformational changes tune reaction pathways across the SN1-SN2 continuum. We highlight recent advances in protein-directed GTs that initiate glycosylation on Ser/Thr, hydroxylysine, Asn, or Arg, and in glycan remodeling GTs that modify mature N-glycans or lipid-linked oligomannose precursors. We also discuss polymerizing and lipid-acceptor GTs that couple catalysis to translocation, scaffolding, or product release. Together, these studies show how transient catalytic states, loop closure, acceptor distortion, and atypical catalytic strategies control reaction trajectory, substrate selectivity, and processivity, while exposing opportunities for inhibition.