Piecing together nonribosomal peptide synthesis

Reimer, Janice M; Haque, Asfarul S.; Tarry, M.J.; Schmeing, T.M.

doi:10.1016/j.sbi.2018.01.011

Cited by 83 publications

(90 citation statements)

References 52 publications

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“…Because of this, signicant efforts have been made in order to understand how NRPS machineries function and the overall structure of these peptide assembly lines. 16 Structural data are available for examples of each catalytic domain from standard NRPS machineriesthese have been obtained either by NMR, X-ray crystallography or a combination of these techniques. Despite the wealth of information derived from structures of isolated domains, understanding NRPS synthesis as a whole requires imaging domain-domain interactions, module-module interactions and even module-module interactions between modules separated across different proteins.…”

Section: Introductionmentioning

confidence: 99%

The many faces and important roles of protein–protein interactions during non-ribosomal peptide synthesis

Izoré

Cryle

2018

Nat. Prod. Rep.

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Covering: up to July 2018 Non-ribosomal peptide synthetase (NRPS) machineries are complex, multi-domain proteins that are responsible for the biosynthesis of many important, peptide-derived compounds. By decoupling peptide synthesis from the ribosome, NRPS assembly lines are able to access a significant pool of amino acid monomers for peptide synthesis. This is combined with a modular protein architecture that allows for great variation in stereochemistry, peptide length, cyclisation state and further modifications. The architecture of NRPS assembly lines relies upon a repetitive set of catalytic domains, which are organised into modules responsible for amino acid incorporation. Central to NRPS-mediated biosynthesis is the carrier protein (CP) domain, to which all intermediates following initial monomer activation are bound during peptide synthesis up until the final handover to the thioesterase domain that cleaves the mature peptide from the NRPS. This mechanism makes understanding the protein-protein interactions that occur between different NRPS domains during peptide biosynthesis of crucial importance to understanding overall NRPS function. This endeavour is also highly challenging due to the inherent flexibility and dynamics of NRPS systems. In this review, we present the current state of understanding of the protein-protein interactions that govern NRPS-mediated biosynthesis, with a focus on insights gained from structural studies relating to CP domain interactions within these impressive peptide assembly lines.

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Section: Introductionmentioning

confidence: 99%

The many faces and important roles of protein–protein interactions during non-ribosomal peptide synthesis

Izoré

Cryle

2018

Nat. Prod. Rep.

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“…It has been established that the adenosine triphosphate (ATP)-dependent synthesis of non-ribosomal peptides (NRP) occurs by means of peptide synthetase, an enzyme complex independent of messenger RNA, transmitting the genetic information from DNA to ribosomes, where the amino acid sequence of protein products of gene expression is determined [61,63,65].…”

Section: Marine Bacteria-an Inexhaustible Source Of Non-ribosomal Synmentioning

confidence: 99%

“…It should be noted that, from an evolutionary aspect, the understanding of non-ribosomal biosynthesis mechanisms has evolved from the erroneous view of peptide synthetase as a precursor of ribosomes, as well as from the discovery of the "thiotemplate" mechanism [62,65] and its revision in connection with the advent of the modern modular-domain "multiple carrier model" [58,63,64]. In the present review, we consider only some of the antimicrobial peptide substances that are products of this biosynthesis pathway, being components of secondary metabolites of marine bacteria.…”

Section: Marine Bacteria-an Inexhaustible Source Of Non-ribosomal Synmentioning

confidence: 99%

The Biotechnological Potential of Secondary Metabolites from Marine Bacteria

Andryukov

Mikhailov

Беседнова

2019

JMSE

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Marine habitats are a rich source of molecules of biological interest. In particular, marine bacteria attract attention with their ability to synthesize structurally diverse classes of bioactive secondary metabolites with high biotechnological potential. The last decades were marked by numerous discoveries of biomolecules of bacterial symbionts, which have long been considered metabolites of marine animals. Many compounds isolated from marine bacteria are unique in their structure and biological activity. Their study has made a significant contribution to the discovery and production of new natural antimicrobial agents. Identifying the mechanisms and potential of this type of metabolite production in marine bacteria has become one of the noteworthy trends in modern biotechnology. This path has become not only one of the most promising approaches to the development of new antibiotics, but also a potential target for controlling the viability of pathogenic bacteria.

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“…Dynamical nature of proteins plays an essential role in driving functional mechanisms . Importance of dynamics in protein function and allostery has been emphasized in innumerable contexts including transport of molecules across cell membrane, assembly of macromolecular complexes, enzyme catalysis and receptor‐mediated signal transduction . Concomitantly, several studies in the last few decades have focused on understanding the complex relationship among three‐dimensional (3D) structure, dynamics, function, and their evolution …”

Section: Introductionmentioning

confidence: 99%

How good are comparative models in the understanding of protein dynamics?

Yazhini

Srinivasan

2020

Proteins

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The 3D structure of a protein is essential to understand protein dynamics. If experimentally determined structure is unavailable, comparative models could be used to infer dynamics. However, the effectiveness of comparative models, compared to experimental structures, in inferring dynamics is not clear. To address this, we compared dynamics features of ~800 comparative models with their crystal structures using normal mode analysis. Average similarity in magnitude, direction, and correlation of residue motions is >0.8 (where value 1 is identical) indicating that the dynamics of models and crystal structures are highly similar. Accuracy of 3D structure and dynamics is significantly higher for models built on multiple and/or high sequence identity templates (>40%). Three‐dimensional (3D) structure and residue fluctuations of models are closer to that of crystal structures than to templates (TM score 0.9 vs 0.7 and square inner product 0.92 vs 0.88). Furthermore, long‐range molecular dynamics simulations on comparative models of RNase 1 and Angiogenin showed significant differences in the conformational sampling of conserved active‐site residues that characterize differences in their activity levels. Similar analyses on two EGFR kinase variant models highlight the effect of mutations on the functional state‐specific αC helix motions and these results corroborate with the previous experimental observations. Thus, our study adds confidence to the use of comparative models in understanding protein dynamics.

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Piecing together nonribosomal peptide synthesis

Cited by 83 publications

References 52 publications

The many faces and important roles of protein–protein interactions during non-ribosomal peptide synthesis

The many faces and important roles of protein–protein interactions during non-ribosomal peptide synthesis

The Biotechnological Potential of Secondary Metabolites from Marine Bacteria

How good are comparative models in the understanding of protein dynamics?

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