Structure and the Mode of Activity of Lon Proteases from Diverse Organisms

Wlodawer, Alexander; Sekula, B.; Gustchina, Alla; Rotanova, T. V.

doi:10.1016/j.jmb.2022.167504

Cited by 21 publications

(19 citation statements)

References 77 publications

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“…This arrangement results in the creation of an expected planar hexamer ( Figure 2 ). Such a hexamer is similar to the hexameric P domains of Ec LonA and Af LonB, to the P domains in the almost full-length hexameric proteases LonB from Thermococcus onnurineus ( Ton LonB) and LonC from Meiothermus taiwanensis ( Mta LonC), as well as in cryoEM structures of full length human mitochondrial LonA ( h MtLonA) (as recently reviewed [ 33 ]). It must be stressed, however, that the protein used for crystallization behaved as a dimer when run on a sizing column before crystallization experiments were set up.…”

Section: Resultsmentioning

confidence: 71%

“…High-resolution crystal structures that include bortezomib-inhibited protease domains are available for h MtLonA (PDB ID 6x27), LonA from M. taiwanensis ( Mta LonA) (4ypm), and Mta LonC (4fwd) [ 33 ]. There are currently no published data available for any LonB complexed with any ligand, including bortezomib.…”

Section: Resultsmentioning

confidence: 99%

“…Definitions of the domain organization of Lon proteases used here follow the recently presented scheme [ 33 ] and are shown in Figure 1 . A polypeptide chain of all Lon proteases contains an ATPase (A) domain followed by a protease (P) domain, and in some cases also additional domains.…”

Section: Introductionmentioning

confidence: 99%

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Unique Structural Fold of LonBA Protease from Bacillus subtilis, a Member of a Newly Identified Subfamily of Lon Proteases

Gustchina

Андрианова

et al. 2022

IJMS

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ATP-dependent Lon proteases are key participants in the quality control system that supports the homeostasis of the cellular proteome. Based on their unique structural and biochemical properties, Lon proteases have been assigned in the MEROPS database to three subfamilies (A, B, and C). All Lons are single-chain, multidomain proteins containing an ATPase and protease domains, with different additional elements present in each subfamily. LonA and LonC proteases are soluble cytoplasmic enzymes, whereas LonBs are membrane-bound. Based on an analysis of the available sequences of Lon proteases, we identified a number of enzymes currently assigned to the LonB subfamily that, although presumably membrane-bound, include structural features more similar to their counterparts in the LonA subfamily. This observation was confirmed by the crystal structure of the proteolytic domain of the enzyme previously assigned as Bacillus subtilis LonB, combined with the modeled structure of its ATPase domain. Several structural features present in both domains differ from their counterparts in either LonA or LonB subfamilies. We thus postulate that this enzyme is the founding member of a newly identified LonBA subfamily, so far found only in the gene sequences of firmicutes.

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Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

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Unique Structural Fold of LonBA Protease from Bacillus subtilis, a Member of a Newly Identified Subfamily of Lon Proteases

Gustchina

Андрианова

et al. 2022

IJMS

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“…The top-scoring binding pose of 12 was characterized by low binding energy (ΔG = −8.8 kcal/mol) and the formation of strong hydrogen bonds with Ser855 and Lys898 which formed the catalytic dyad of LonP1 [ 72 ]. Additionally, the triterpenoid core of 12 was stabilized by a hydrogen bond with Asp852 ( Figure 6 G), playing an important role in the enzymatic activity of LonP1 [ 73 ].…”

Section: Resultsmentioning

confidence: 99%

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

et al. 2022

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The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC50(24 h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment.

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“…In addition to the genomes of putative tryptorubin producers, genomes of frequently used bacterial heterologous host strains were likewise mined for all genes annotated as proteases or peptidases to identify suitable host strains for subsequent heterologous expression studies of the putative minimal trp BGC. Phylogenetic analyses revealed that putative producers of tryptorubin‐like peptides encode members of four conserved protease families, three of which (M41 family of unassigned peptidases, [13] S16 family of unassigned peptidases [14] and AA223 family of peptidases [13] ) belong to the superfamily of AAA+ proteases that are intracellular, membrane‐associated enzymes that catalyze the degradation of a wide range of proteins. Moreover, members of the family of M24B unassigned extracellular metallo‐peptidases [15] were identified in all putative tryptorubin producers and all commonly used Streptomyces host strains (Figure S3).…”

Section: Figurementioning

confidence: 99%

Atropopeptides are a Novel Family of Ribosomally Synthesized and Posttranslationally Modified Peptides with a Complex Molecular Shape

et al. 2022

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Biomacromolecules are known to feature complex three-dimensional shapes that are essential for their function. Among natural products, ambiguous molecular shapes are a rare phenomenon. The hexapeptide tryptorubin A can adopt one of two unusual atropisomeric configurations. Initially hypothesized to be a non-ribosomal peptide, we show that tryptorubin A is the first characterized member of a new family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) that we named atropopeptides. The sole modifying enzyme encoded in the gene cluster, a cytochrome P450 monooxygenase, is responsible for the atropospecific formation of one carbon-carbon and two carbon-nitrogen bonds. The characterization of two additional atropopeptide biosynthetic pathways revealed a two-step maturation process. Atropopeptides promote pro-angiogenic cell functions as indicated by an increase in endothelial cell proliferation and undirected migration. Our study expands the biochemical space of RiPPmodifying enzymes and paves the way towards the chemoenzymatic utilization of atropopeptide-modifying P450s.

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Structure and the Mode of Activity of Lon Proteases from Diverse Organisms

Cited by 21 publications

References 77 publications

Unique Structural Fold of LonBA Protease from Bacillus subtilis, a Member of a Newly Identified Subfamily of Lon Proteases

Unique Structural Fold of LonBA Protease from Bacillus subtilis, a Member of a Newly Identified Subfamily of Lon Proteases

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

Atropopeptides are a Novel Family of Ribosomally Synthesized and Posttranslationally Modified Peptides with a Complex Molecular Shape

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