8YE0

Crystal structure of KgpF prenyltransferase

Summary for 8YE0

• Entry DOI: 10.2210/pdb8ye0/pdb
• Descriptor: LynF/TruF/PatF family peptide O-prenyltransferase, TRIHYDROGEN THIODIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: ripp, prenylation, prenyltransferase, abba fold, transferase
• Biological source: Microcystis aeruginosa NIES-88
• Total number of polymer chains: 4
• Total formula weight: 137805.30

Authors

Hamada, K.,Inoue, S.,Goto, Y.,Suga, H.,Ogata, K.,Sengoku, T. (deposition date: 2024-02-21, release date: 2024-06-19, Last modification date: 2024-09-11)

Primary citation

Inoue, S.,Thanh Nguyen, D.,Hamada, K.,Okuma, R.,Okada, C.,Okada, M.,Abe, I.,Sengoku, T.,Goto, Y.,Suga, H.
De Novo Discovery of Pseudo-Natural Prenylated Macrocyclic Peptide Ligands.
Angew.Chem.Int.Ed.Engl., 63:e202409973-e202409973, 2024

PubMed Abstract: Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC of 30 nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets.

PubMed: 38837490
DOI: 10.1002/anie.202409973

Experimental method

X-RAY DIFFRACTION (1.94 Å)