| Structural highlights
Function
OPHMA_OMPOL Fusion protein of the methyltransferase ophM and the omphalotin core peptide; part of the gene cluster that mediates the biosynthesis of omphalotin A, a highly methylated cyclic dodecapeptide with nematodicidal activity (PubMed:28715095, PubMed:30151425, PubMed:32491837, PubMed:33574430). Omphalotin A derives from the C-terminus of the ophMA protein, and it is the ophMA protein that methylates its own C-terminus using S-adenosyl methionine (SAM) (PubMed:28715095, PubMed:30151425, PubMed:32491837, PubMed:33574430). The C-terminus is subsequently cleaved off and macrocyclized by the prolyloligopeptidase ophP to give the final product (PubMed:28715095, PubMed:30151425, PubMed:32491837).[1] [2] [3] [4]
Publication Abstract from PubMed
The biological activities and pharmacological properties of peptides and peptide mimetics are determined by their conformational states. Therefore, a detailed understanding of the conformational landscape is crucial for rational drug design. Nuclear magnetic resonance (NMR) is the only method for structure determination in solution. However, it remains challenging to determine the structures of peptides using NMR because of very weak nuclear Overhauser effects (NOEs), the semiquantitative nature of the rotating frame Overhauser effect (ROE), and the low number of NOEs/ROEs in N-methylated peptides. In this study, we introduce a new approach to investigating the structures of modified macrocyclic peptides. We utilize exact NOEs (eNOEs) in viscous solvent mixtures to replicate various cellular environments. eNOEs provide detailed structural information for highly dynamic modified peptides. Structures of high precision were obtained for cyclosporin A, with a backbone atom rmsd of 0.10 A. Distinct conformational states in different environments were identified for omphalotin A (OmphA), a fungal nematotoxic and multiple backbone N-methylated macrocyclic peptides. A model for cell-permeation is presented for OmphA, based on its structures in polar, apolar, and mixed polarity solvents. During the transition from a polar to an apolar environment, OmphA undergoes a rearrangement of its H-bonding network, accompanied by a cis to trans isomerization of the omega torsion angle within a type VIa beta-turn. We hypothesize that the kinetics of these conformational transitions play a crucial role in determining the membrane-permeation capabilities of OmphA.
Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability.,Rudisser SH, Matabaro E, Sonderegger L, Guntert P, Kunzler M, Gossert AD J Am Chem Soc. 2023 Dec 20;145(50):27601-27615. doi: 10.1021/jacs.3c09367. Epub , 2023 Dec 7. PMID:38062770[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ramm S, Krawczyk B, Mühlenweg A, Poch A, Mösker E, Süssmuth RD. A Self-Sacrificing N-Methyltransferase Is the Precursor of the Fungal Natural Product Omphalotin. Angew Chem Int Ed Engl. 2017 Aug 7;56(33):9994-9997. PMID:28715095 doi:10.1002/anie.201703488
- ↑ Song H, van der Velden NS, Shiran SL, Bleiziffer P, Zach C, Sieber R, Imani AS, Krausbeck F, Aebi M, Freeman MF, Riniker S, Kunzler M, Naismith JH. A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds. Sci Adv. 2018 Aug 24;4(8):eaat2720. doi: 10.1126/sciadv.aat2720. eCollection 2018, Aug. PMID:30151425 doi:http://dx.doi.org/10.1126/sciadv.aat2720
- ↑ Song H, Fahrig-Kamarauskaite JR, Matabaro E, Kaspar H, Shirran SL, Zach C, Pace A, Stefanov BA, Naismith JH, Kunzler M. Substrate Plasticity of a Fungal Peptide alpha-N-Methyltransferase. ACS Chem Biol. 2020 Jun 19. doi: 10.1021/acschembio.0c00237. PMID:32491837 doi:http://dx.doi.org/10.1021/acschembio.0c00237
- ↑ Matabaro E, Kaspar H, Dahlin P, Bader DLV, Murar CE, Staubli F, Field CM, Bode JW, Künzler M. Identification, heterologous production and bioactivity of lentinulin A and dendrothelin A, two natural variants of backbone N-methylated peptide macrocycle omphalotin A. Sci Rep. 2021 Feb 11;11(1):3541. PMID:33574430 doi:10.1038/s41598-021-83106-2
- ↑ Rüdisser SH, Matabaro E, Sonderegger L, Güntert P, Künzler M, Gossert AD. Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability. J Am Chem Soc. 2023 Dec 20;145(50):27601-27615. PMID:38062770 doi:10.1021/jacs.3c09367
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