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Mechanistic insights into the slow peptide bond formation with D-amino acids in the ribosomal active site

Lookup NU author(s): Dr Sergey MelnikovORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 The Author(s).During protein synthesis, ribosomes discriminate chirality of amino acids and prevent incorporation of D-amino acids into nascent proteins by slowing down the rate of peptide bond formation. Despite this phenomenon being known for nearly forty years, no structures have ever been reported that would explain the poor reactivity of D-amino acids. Here we report a 3.7A-resolution crystal structure of a bacterial ribosome in complex with a D-aminoacyl-tRNA analog bound to the A site. Although at this resolution we could not observe individual chemical groups, we could unambiguously define the positions of the Damino acid side chain and the amino group based on chemical restraints. The structure reveals that similarly to L-amino acids, the D-amino acid binds the ribosome by inserting its side chain into the ribosomal A-site cleft. This binding mode does not allow optimal nucleophilic attack of the peptidyl-tRNA by the reactive -amino group of a D-amino acid. Also, our structure suggests that the D-amino acid cannot participate in hydrogen-bonding with the P-site tRNA that is required for the efficient proton transfer during peptide bond formation. Overall, our work provides the first mechanistic insight into the ancient mechanism that helps living cells ensure the stereochemistry of protein synthesis.

Publication metadata

Author(s): Melnikov SV, Khabibullina NF, Mairhofer E, Vargas-Rodriguez O, Reynolds NM, Micura R, Soll D, Polikanov YS

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2019

Volume: 47

Issue: 4

Pages: 2089-2100

Print publication date: 28/02/2018

Online publication date: 06/12/2018

Acceptance date: 20/11/2018

Date deposited: 15/07/2020

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press


DOI: 10.1093/nar/gky1211

PubMed id: 30520988


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