Stereochemistry in the disorder-order continuum of protein interactions.

Autor: Newcombe EA; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Due AD; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Sottini A; Department of Biochemistry and Department of Physics, University of Zurich, Zurich, Switzerland., Elkjær S; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Theisen FF; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Fernandes CB; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Staby L; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Delaforge E; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Bartling CRO; Department of Drug Design and Pharmacology, Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark., Brakti I; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Bugge K; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Schuler B; Department of Biochemistry and Department of Physics, University of Zurich, Zurich, Switzerland., Skriver K; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark., Olsen JG; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. joe@bio.ku.dk.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. joe@bio.ku.dk.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. joe@bio.ku.dk., Kragelund BB; REPIN, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. bbk@bio.ku.dk.; Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. bbk@bio.ku.dk.; Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen N, Denmark. bbk@bio.ku.dk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Dec; Vol. 636 (8043), pp. 762-768. Date of Electronic Publication: 2024 Nov 27.
DOI: 10.1038/s41586-024-08271-6
Abstrakt: Intrinsically disordered proteins can bind via the formation of highly disordered protein complexes without the formation of three-dimensional structure 1 . Most naturally occurring proteins are levorotatory (L)-that is, made up only of L-amino acids-imprinting molecular structure and communication with stereochemistry 2 . 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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