Abstract
Graspetides, also known as ω-ester-containing peptides (OEPs), are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing side chain-to-side chain macrolactone or macrolactam linkages. Here, we present the molecular details of precursor peptide recognition by the macrocyclase enzyme PsnB in the biosynthesis of plesiocin, a group 2 graspetide. Biochemical analysis revealed that, in contrast to other RiPPs, the core region of the plesiocin precursor peptide noticeably enhanced the enzyme–precursor interaction via the conserved glutamate residues. We obtained four crystal structures of symmetric or asymmetric PsnB dimers, including those with a bound core peptide and a nucleotide, and suggest that the highly conserved Arg213 at the enzyme active site specifically recognizes a ring-forming acidic residue before phosphorylation. Collectively, this study provides insights into the mechanism underlying substrate recognition in graspetide biosynthesis and lays a foundation for engineering new variants.
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Data availability
Coordinates and structure factors for the reported crystal structures in this work were deposited in the RCSB PDB under accession numbers 7DRM (MP- and ADP-bound PsnB), 7DRN (MP- and AMPPNP-bound PsnB), 7DRP (MP(pE37)- and ADP-bound PsnB) and 7DRO (MP-bound PsnB). Source data are provided with this paper.
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Acknowledgements
We thank H. Lee, G. Eom, C. Lee, H. Roh, H. Cho and H. Park for helpful discussions and technical assistance, H. Chung, Y.J. Lee and T.Y. Im for assistance in synthesizing compounds, Y.T. Kim, W.J. Jeong and Y. Choi for advice in crystallization and crystallographic analysis and H. Woo for help in loop modeling. We also thank the staff of the 5C and 7A beamlines at the Pohang Light Source. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1F1A1054191 and 2021R1A2C1008730) to S.K.
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I.S. and S.K. conceived the project, designed experiments, analyzed data and wrote the paper. S.K. supervised the project. I.S. performed the majority of experiments. Y.K. performed a part of the mutant analysis. I.S. and J.Y. conducted crystallographic experiments under the supervision of W.J.S. and S.K. I.S. and S.Y.G. synthesized the phosphomimetic glutamate under the supervision of H.G.L. and S.K.
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Extended data
Extended Data Fig. 1 Designed minimal precursor recapitulates the reactivity of PsnB.
a, Sequence logo of precursors of Group 2a graspetides including the leader peptide (red region) and one core motif (blue region). The LFIEDL region is highly conserved in Group 2a graspetides (yellow box). b,c, ATPase assays titrating with ATP (b) in solutions containing 0.4 μM PsnB, 200 μM minimal precursor (MP), 100 mM Tris pH 7.3, 50 mM KCl, and 10 mM MgCl2, or titrating with MgCl2 (c) in solutions containing 0.4 μM PsnB, 200 μM MP, 100 mM Tris pH 7.3, 50 mM KCl, and 5 mM ATP. Data are presented as dot plots with mean ± 1 SD (n = 3 independent experiments) and fitted to a hyperbolic equation. d, Minimal precursor was successfully modified by PsnB with a modification rate similar to that of wild-type PsnA2. 50 μM MP (top panel; the product contains two ester bonds) or wild-type PsnA2 (bottom panel; the product contains eight ester bonds) was co-incubated with 0.5 μM PsnB in buffer A (100 mM Tris pH 7.3, 50 mM KCl, 5 mM ATP, and 10 mM MgCl2) at 37 °C, and the reaction solutions at designated time points were analyzed by MALDI-MS.
Extended Data Fig. 2 Acyl-phosphate intermediates were trapped by hydroxylamine.
a, Scheme of the acyl-phosphate trapping during the macrocyclization reaction. Nucleophilic attack of hydroxylamine rather than the core threonine generates the hydroxylamine adducts of the precursor. b, MALDI analysis of the reaction solution with (left) or without (right) hydroxylamine. 0.5 M hydroxylamine was added to the reaction mixture containing 100 μM MP (1-a) and 6 μM PsnB in buffer A. The reaction mixtures were analyzed by MALDI after 4 hour incubation at 37 °C. Co-incubation of 0.5 M hydroxylamine generated NH2OH-added precursor peptides (1-b and 2-b), which are the result of nucleophilic attack of hydroxylamine to acyl-phosphate intermediates. c, 2-b was purified by HPLC and methanolysis was performed with purified 2-b as previously reported26. The methanolysis product (2-c) was detected by MALDI. d, MALDI-MS/MS analysis of three hydroxylamine adducts. The connectivities of ester bonds were determined by MS/MS analysis with NH2OH-added precursor peptides (1-b and 2-b) and methanolysis product (2-c).
Extended Data Fig. 3 Binding of the leader peptide activates PsnB.
a, LP (PsnA214-24) enhances the affinity of the CP (PsnA228-38) to PsnB. Fraction bound of Fl_CP (0.1 µM) to PsnB (50 µM) was determined by fluorescence anisotropy. b, LP enhances the ATPase activity of PsnB. Basal ATP consumption rate of PsnB was 0.14 min-1enz-1, whereas the addition of 200 μM LP increased the ATP consumption rate to 0.89 min-1enz-1. P value < 0.01 by two-sided Student’s t-test. c, Fluorescence anisotropy of Fl_LP (0.1 µM) to wild-type PsnB or leader-fused PsnB (LP_PsnB). Data are presented as dot plots with mean ± 1 SD (n = 3 independent experiments; a-c) and fitted to a hyperbolic equation (c).
Extended Data Fig. 4 Binding and modification of ring-containing precursors.
a,b, Affinity of ring-containing MPs (MP-1H2O, the single-ring intermediate; MP-2H2O, the double-ring product) to PsnB was determined by fluorescence anisotropy without nucleotide (a) or with 1 mM ADP (b). c, ATPase activity of PsnB was measured with different concentrations of MP or the single-ring intermediate (MP-1H2O). Data are presented as dot plots with mean ± 1 SD (n = 3 independent experiments; a-c) and fitted to a hyperbolic equation (a-c).
Extended Data Fig. 5 Four crystal structures of PsnB complexes.
Structure of four different states of PsnB dimers (E, enzyme, yellow or pale cyan cartoon; N, nucleotide, cyan sticks; L, leader, magenta sticks; C, core, green sticks). Polder OMIT map (gray mesh) of each peptide or nucleotide is contoured at 4.0 σ.
Extended Data Fig. 6 Polder OMIT maps that are calculated without the model for LP, CP, or nucleotide (contour level at 4.0 σ).
For the LP and CP, resolved residues are listed on Supplementary Table 2. Phospho-mimetic side-chain in CP is only resolved well in chain E of 7DRP.
Extended Data Fig. 7 No higher oligomers were observed from PsnB.
a, Gel-filtration chromatogram of PsnB without MgCl2 (black solid line), with MgCl2 (red solid line), or with both MgCl2 and ATP (blue solid line). A chromatogram of molecular weight standard (black dashed line) is also shown with known molecular weights. Addition of nucleotide did not induce the formation of the stable higher oligomer of PsnB dimer. b‒e, FRET of a solution containing both donor- and acceptor-labeled PsnB was measured with different amounts of MgCl2 (b), AMPPNP (c), LP (d), or MP (e). Additional components in solutions are listed above the plots. Neither nucleotide nor precursor induced stable intermolecular interaction of PsnB. f, Loop modeling revealed that β13β14 loop is long and flexible enough for intramolecular interaction. Residues between Ile227 and Ile247, the β13β14 loop region, were modeled by FALC59,60 and overall complex structure was optimized by relaxation. In the modeled structure, the conformation of the β13β14 loop was flipped and the DFR motif moved toward the enzyme active site. Also, Arg235 had hydrogen bonding with nucleotide which is similar to the intermolecular interaction scheme shown in crystal structures (Fig. 4c).
Extended Data Fig. 8 Binding property of core-binding site mutants of leader-fused PsnB.
Fluorescence anisotropy of Fl_CP (0.1 µM) with leader-fused PsnB mutants. Mutation of core-binding residues reduced the affinity between CP and the enzyme. Data are presented as dot plots with mean ± 1 SD (n = 3 independent experiments) and fitted to a hyperbolic equation.
Extended Data Fig. 9 Molecular interaction, binding affinity, and inhibition effect of MP(pE37).
a, Detailed interaction scheme of MP(pE37) and PsnB. pGlu37 makes no interaction, whereas Glu38 interacts with Arg213 (yellow sticks) of PsnB. b, Binding affinity of Fl-MP(pE37) to PsnB was measured by fluorescence anisotropy. MP(pE37) binds less tightly to PsnB than the MP no matter whether ADP is present. Data are presented as dot plots with mean ± 1 SD (n = 3 independent experiments) and fitted to a hyperbolic equation. c, Inhibition assay was performed with MP(pE37) or LP. 10 μM MP and 0.4 μM PsnB was co-incubated with various concentrations of MP(pE37) (left) or LP (right) in a buffer containing Tris-HCl (100 mM; pH 7.3), MgCl2 (10 mM), KCl (50 mM) and ATP (5 mM) at 37 °C for 10 min.
Extended Data Fig. 10 Precursor and nucleotide binding induces conformational change of PsnB.
a, Surface models of the leader-binding domain without (left) or with (right) the bound Phe15 in the LP (magenta sticks). Hydrophobic pocket for Phe15 is shown as magenta dashed lines. b, The nucleotide (cyan sticks) binding shifts the β9β10 loop (from gray to yellow cartoon). Lys172 and Thr180 that interact with a nucleotide are shown as green sticks. c, Two α3α4 pairs of a PsnB dimer show extensive interactions to each other to form a rigid body. Two PsnB subunits are shown as yellow and pale cyan cartoons, and their interacting residues are presented as orange and cyan sticks, respectively. d, Surface model of the ENLC-E complex (yellow and pale cyan for two PsnB subunits). Binding of LP (magenta) and nucleotide (cyan spheres) induces the conformational change of PsnB dimer to generate a compact core (green) binding site. e, Superposition of four LP and CP pairs from PsnB-MP-ADP (7DRM, green and cyan ribbons) and PsnB-MP-AMPPNP (7DRN, magenta and yellow ribbons). All LPs and CPs are well overlapped. PsnB is shown as gray cartoon and half-transparent surface. Nucleotide and Arg213 are shown as gray sticks. Glu37 in CP is shown as sticks.
Supplementary information
Supplementary Information
Supplementary Figs. 1–6, Tables 1–5 and Note.
Supplementary Video 1
Supplementary Video 1
Source data
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Statistical source data for Fig. 1d,e.
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Statistical source data for Fig. 2a,b,d–f.
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Statistical source data for Extended Data Fig. 7b–e.
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Statistical source data for Extended Data Fig. 9b.
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Song, I., Kim, Y., Yu, J. et al. Molecular mechanism underlying substrate recognition of the peptide macrocyclase PsnB. Nat Chem Biol 17, 1123–1131 (2021). https://doi.org/10.1038/s41589-021-00855-x
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DOI: https://doi.org/10.1038/s41589-021-00855-x
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