High‐Resolution Crystal Structure of a Lasso Peptide

Nar, Herbert; Schmid, Alex P.; Puder, Carsten; Potterat, Olivier

doi:10.1002/cmdc.201000264

Cited by 38 publications

(34 citation statements)

References 28 publications

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“…RP-71955, the siamycins, and BI-32169, like STM, contain 5% hydrophilic and 43–53% hydrophobic residues, being rich in Leu/Ile/Val/Ala (Table S4). Additionally, despite little primary sequence identity, the structure of STM aligns closely (backbone rmsd 1.03 Å for residues 1–17 against lowest energy conformer of STM) to the crystal structure of BI-32169 (PDB code 3NJW), a lasso peptide of streptomycete origin (Knappe et al, 2010; Nar et al, 2010) (Figure S5B). …”

Section: Resultsmentioning

confidence: 70%

Structure, Bioactivity, and Resistance Mechanism of Streptomonomicin, an Unusual Lasso Peptide from an Understudied Halophilic Actinomycete

Metelev¹,

Tietz²,

Melby³

et al. 2015

Chemistry & Biology

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Summary Natural products are the most historically significant source of compounds for drug development. However, unacceptably high rates of compound rediscovery associated with large-scale screening of common microbial producers have resulted in the abandonment of many natural product drug discovery efforts, despite the increasing prevalence of clinically-problematic antibiotic resistance. Screening of underexplored taxa represents one strategy to avoid rediscovery. Herein we report the discovery, isolation, and structural elucidation of streptomonomicin (STM), an antibiotic lasso peptide from Streptomonospora alba, and report the genome for its producing organism. STM-resistant clones of Bacillus anthracis harbor mutations to walR, the gene encoding a response regulator for the only known widely-distributed and essential two-component signal transduction system in Firmicutes. Streptomonospora had been hitherto biosynthetically and genetically uncharacterized, with STM being the first reported compound from the genus. Our results demonstrate that understudied microbes remain fruitful reservoirs for the rapid discovery of novel, bioactive natural products.

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Section: Resultsmentioning

confidence: 70%

Structure, Bioactivity, and Resistance Mechanism of Streptomonomicin, an Unusual Lasso Peptide from an Understudied Halophilic Actinomycete

Metelev¹,

Tietz²,

Melby³

et al. 2015

Chemistry & Biology

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“…The known structures of AMPs are classified into four families (α, β, αβ, and non-αβ) [26] and the structural family for each peptide is indicated at the left bottom corner of each panel. The PDB IDs and references for these structures are: ( A ) 1VM5 [50] for aurein 1.2 in complex with SDS micelles; ( B ) 2K6O for human cathelcidin LL-37 in complex with SDS micelles [71]; ( C ) 1XKM for amphibian distinctin in water [114]; ( D ) 2JS9 for caenopore-5 [115] from Caenorhabditis elegans ; ( E ) 3NJW for BI-32169 as a representative lasso structure [116]; ( F ) 2LYF for θ-defensin RTD-1 [117,118]; ( G ) 1KAL for plant kalata B1 [119]; ( H ) 3GNY for human α-defensin 1 (or human neutrophil peptide-1; HNP-1) [120]; ( I ) 1ZFU for fungal plectasin [80]; ( J ) 1FJN for mussel MGD-1 [121]; ( K ) 1E4S for human beta defensin 1 (HBD-1) [122]; and ( L ) 1G89 for bovine indolicidin [123]. Structural coordinates were obtained from the RCSB Protein Data Bank (PDB) [124].…”

Section: Structural Annotation Classification and Determination Omentioning

confidence: 99%

“…In the APD, various three-dimensional structures [50,71,114,115,116,117,118,119,120,121,122,123] are classified into four families: α, β, αβ, and non-αβ (see Figure 4) based on the presence or absence of secondary structures such as α-helix and β-sheet [26]. The α family consists of AMPs with α-helical structures (Figure 4, Panels A–D).…”

Section: Structural Annotation Classification and Determination Omentioning

confidence: 99%

Database-Guided Discovery of Potent Peptides to Combat HIV-1 or Superbugs

Wang

2013

Pharmaceuticals

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Antimicrobial peptides (AMPs), small host defense proteins, are indispensable for the protection of multicellular organisms such as plants and animals from infection. The number of AMPs discovered per year increased steadily since the 1980s. Over 2,000 natural AMPs from bacteria, protozoa, fungi, plants, and animals have been registered into the antimicrobial peptide database (APD). The majority of these AMPs (>86%) possess 11–50 amino acids with a net charge from 0 to +7 and hydrophobic percentages between 31–70%. This article summarizes peptide discovery on the basis of the APD. The major methods are the linguistic model, database screening, de novo design, and template-based design. Using these methods, we identified various potent peptides against human immunodeficiency virus type 1 (HIV-1) or methicillin-resistant Staphylococcus aureus (MRSA). While the stepwise designed anti-HIV peptide is disulfide-linked and rich in arginines, the ab initio designed anti-MRSA peptide is linear and rich in leucines. Thus, there are different requirements for antiviral and antibacterial peptides, which could kill pathogens via different molecular targets. The biased amino acid composition in the database-designed peptides, or natural peptides such as θ-defensins, requires the use of the improved two-dimensional NMR method for structural determination to avoid the publication of misleading structure and dynamics. In the case of human cathelicidin LL-37, structural determination requires 3D NMR techniques. The high-quality structure of LL-37 provides a solid basis for understanding its interactions with membranes of bacteria and other pathogens. In conclusion, the APD database is a comprehensive platform for storing, classifying, searching, predicting, and designing potent peptides against pathogenic bacteria, viruses, fungi, parasites, and cancer cells.

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“…; 5 and RES-701-1, BI-32169, siamycin I (also known as MS-271, NP-06, and FR901724 ), siamycin II, and siamycin III (also known as RP71955 and aborycin) from Streptomyces spp. 6–12 Depending on structural features including the presence or the absence of sets of cysteine residues, which can be involved in the formation of up to two intramolecular disulfide bonds, threaded-lasso peptides are divided into two classes: “class I” threaded-lasso peptides have disulfide bonds (siamycins I-III), and “class II” threaded-lasso peptides lacking disulfide bonds (MccJ25, capistruin, lariatin A, and lariatin B). BI-32169 unites structural features of class I and II and was recently proposed to form a third class of threaded lasso peptides.…”

Section: Introductionmentioning

confidence: 99%

The Antibacterial Threaded-lasso Peptide Capistruin Inhibits Bacterial RNA Polymerase

Kuznedelov

Semenova

Knappe

et al. 2011

Journal of Molecular Biology

101

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SUMMARY Capistruin, a ribosomally synthesized post-translationally modified peptide produced by Burkholderia thailandensis E264, efficiently inhibits growth of Burkholderia and closely related Pseudomonas strains. The functional target of capistruin is unknown. Capistruin is a threaded-lasso peptide (lariat peptide), comprising an N-terminal 9-amino-acid ring followed by a 10-amino-acid C-terminal tail that is threaded through the ring. The structure of capistruin is similar to that of microcin J25 (MccJ25), a threaded-lasso antibacterial peptide that is produced by some strains of Escherichia coli and targets DNA-dependent RNA polymerase (RNAP). Here, we show that capustruin, like MccJ25, inhibits wild-type E. coli RNAP but not mutant, MccJ25-resistant, E. coli RNAP. We show further that an E. coli strain resistant to MccJ25 due to a mutation in an RNAP subunit gene exhibits resistance to capistruin. The results indicate that the structural similarity of capistruin and MccJ25 reflects functional similarity and suggest that the functional target of capistruin, and possibly other threaded-lasso peptides, is bacterial RNAP.

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High‐Resolution Crystal Structure of a Lasso Peptide

Cited by 38 publications

References 28 publications

Structure, Bioactivity, and Resistance Mechanism of Streptomonomicin, an Unusual Lasso Peptide from an Understudied Halophilic Actinomycete

Structure, Bioactivity, and Resistance Mechanism of Streptomonomicin, an Unusual Lasso Peptide from an Understudied Halophilic Actinomycete

Database-Guided Discovery of Potent Peptides to Combat HIV-1 or Superbugs

The Antibacterial Threaded-lasso Peptide Capistruin Inhibits Bacterial RNA Polymerase

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