8YE0

Crystal structure of KgpF prenyltransferase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

Starting Model: experimental
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This is version 1.1 of the entry. See complete history


Literature

De Novo Discovery of Pseudo-Natural Prenylated Macrocyclic Peptide Ligands.

Inoue, S.Thanh Nguyen, D.Hamada, K.Okuma, R.Okada, C.Okada, M.Abe, I.Sengoku, T.Goto, Y.Suga, H.

(2024) Angew Chem Int Ed Engl 63: e202409973-e202409973

  • DOI: https://doi.org/10.1002/anie.202409973
  • Primary Citation of Related Structures:  
    8YE0

  • 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 IC50 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.


  • Organizational Affiliation

    The University of Tokyo, Department of Chemistry, JAPAN.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
LynF/TruF/PatF family peptide O-prenyltransferase
A, B, C, D
290Microcystis aeruginosa NIES-88Mutation(s): 0 
Gene Names: EWV68_12770
UniProt
Find proteins for A0A551Z2V8 (Microcystis sp. M_QC_C_20170808_M9Col)
Explore A0A551Z2V8 
Go to UniProtKB:  A0A551Z2V8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A551Z2V8
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BTB
Query on BTB

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C],
P [auth D]
2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C8 H19 N O5
OWMVSZAMULFTJU-UHFFFAOYSA-N
PIS (Subject of Investigation/LOI)
Query on PIS

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
TRIHYDROGEN THIODIPHOSPHATE
H3 O6 P2 S
HWTUHTNZLQJJEV-UHFFFAOYSA-M
MG (Subject of Investigation/LOI)
Query on MG

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
O [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.681α = 109.115
b = 69.344β = 93.102
c = 86.426γ = 104.888
Software Package:
Software NamePurpose
PHENIXrefinement
MrBUMPphasing
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-06-19
    Type: Initial release
  • Version 1.1: 2024-09-11
    Changes: Database references