TY - JOUR
T1 - Stereochemistry in the disorder-order continuum of protein interactions
AU - Newcombe, Estella A
AU - Due, Amanda D
AU - Sottini, Andrea
AU - Elkjær, Steffie
AU - Theisen, Frederik Friis
AU - Fernandes, Catarina B
AU - Staby, Lasse
AU - Delaforge, Elise
AU - Bartling, Christian R O
AU - Brakti, Inna
AU - Bugge, Katrine
AU - Schuler, Benjamin
AU - Skriver, Karen
AU - Olsen, Johan G
AU - Kragelund, Birthe B
N1 - © 2024. The Author(s).
PY - 2024
Y1 - 2024
N2 - Intrinsically disordered proteins can bind via the formation of highly disordered protein complexes without the formation of three-dimensional structure1. Most naturally occurring proteins are levorotatory (L)-that is, made up only of L-amino acids-imprinting molecular structure and communication with stereochemistry2. By contrast, their mirror-image dextrorotatory (D)-amino acids are rare in nature. Whether disordered protein complexes are truly independent of chiral constraints is not clear. Here, to investigate the chiral constraints of disordered protein-protein interactions, we chose as representative examples a set of five interacting protein pairs covering the disorder-order continuum. By observing the natural ligands and their stereochemical mirror images in free and bound states, we found that chirality was inconsequential in a fully disordered complex. However, if the interaction relied on the ligand undergoing extensive coupled folding and binding, correct stereochemistry was essential. Between these extremes, binding could be observed for the D-ligand with a strength that correlated with disorder in the final complex. These findings have important implications for our understanding of the molecular processes that lead to complex formation, the use of D-peptides in drug discovery and the chemistry of protein evolution of the first living entities on Earth.
AB - Intrinsically disordered proteins can bind via the formation of highly disordered protein complexes without the formation of three-dimensional structure1. Most naturally occurring proteins are levorotatory (L)-that is, made up only of L-amino acids-imprinting molecular structure and communication with stereochemistry2. By contrast, their mirror-image dextrorotatory (D)-amino acids are rare in nature. Whether disordered protein complexes are truly independent of chiral constraints is not clear. Here, to investigate the chiral constraints of disordered protein-protein interactions, we chose as representative examples a set of five interacting protein pairs covering the disorder-order continuum. By observing the natural ligands and their stereochemical mirror images in free and bound states, we found that chirality was inconsequential in a fully disordered complex. However, if the interaction relied on the ligand undergoing extensive coupled folding and binding, correct stereochemistry was essential. Between these extremes, binding could be observed for the D-ligand with a strength that correlated with disorder in the final complex. These findings have important implications for our understanding of the molecular processes that lead to complex formation, the use of D-peptides in drug discovery and the chemistry of protein evolution of the first living entities on Earth.
U2 - 10.1038/s41586-024-08271-6
DO - 10.1038/s41586-024-08271-6
M3 - Journal article
C2 - 39604735
VL - 636
SP - 762
EP - 768
JO - Nature
JF - Nature
SN - 0028-0836
ER -