Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance

Pandurangan, Arun Prasad; Ascher, David B.; Thomas, S.E.; Blundell, Tom L.

doi:10.1042/bst20160422

Cited by 35 publications

(22 citation statements)

References 61 publications

(68 reference statements)

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“…Given the medical importance of PlsY, previous studies have synthesized and screened a panel of acylP analogous, and identified several acyl-sulfamates as potential PlsY-inhibiting antimicrobials for Staphylococcus aureus 8 – 10 . Such drug-discovery studies would benefit from virtual screening, where large libraries of small molecules are assessed relatively quickly and inexpensively in silico , compared with the experimental high-throughput screening approach 11 . However, virtual screening relies on high-resolution structures to provide atomic details of regions of interest, which are generally the active site or allosteric regulation sites of target proteins 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Such drug-discovery studies would benefit from virtual screening, where large libraries of small molecules are assessed relatively quickly and inexpensively in silico , compared with the experimental high-throughput screening approach 11 . However, virtual screening relies on high-resolution structures to provide atomic details of regions of interest, which are generally the active site or allosteric regulation sites of target proteins 11 .…”

Section: Introductionmentioning

confidence: 99%

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Structural insights into the committed step of bacterial phospholipid biosynthesis

Tang

et al. 2017

Nat Commun

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The membrane-integral glycerol 3-phosphate (G3P) acyltransferase PlsY catalyses the committed and essential step in bacterial phospholipid biosynthesis by acylation of G3P, forming lysophosphatidic acid. It contains no known acyltransferase motifs, lacks eukaryotic homologs, and uses the unusual acyl-phosphate as acyl donor, as opposed to acyl-CoA or acyl-carrier protein for other acyltransferases. Previous studies have identified several PlsY inhibitors as potential antimicrobials. Here we determine the crystal structure of PlsY at 1.48 Å resolution, revealing a seven-transmembrane helix fold. Four additional substrate- and product-bound structures uncover the atomic details of its relatively inflexible active site. Structure and mutagenesis suggest a different acylation mechanism of ‘substrate-assisted catalysis’ that, unlike other acyltransferases, does not require a proteinaceous catalytic base to complete. The structure data and a high-throughput enzymatic assay developed in this work should prove useful for virtual and experimental screening of inhibitors against this vital bacterial enzyme.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural insights into the committed step of bacterial phospholipid biosynthesis

Tang

et al. 2017

Nat Commun

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“…This is a crucial step in order to identify the most important regions for protein functionality and thus to understand the effects that mutations associated with retinal disease might have on it. Mutations occurring in a conserved site are assumed to have a greater impact on the correct protein folding 77,78 and, consequently, to alter its functionality. Indeed, phylogenetically conserved sequences in divergent species probably identify a protein region of extreme importance for structural stability.…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

Trezza

Bernini

Langella

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The aim of this article is to report the investigation of the structural features of ABCA4, a protein associated with a genetic retinal disease. A new database collecting knowledge of ABCA4 structure may facilitate predictions about the possible functional consequences of gene mutations observed in clinical practice. METHODS.In order to correlate structural and functional effects of the observed mutations, the structure of mouse P-glycoprotein was used as a template for homology modeling. The obtained structural information and genetic data are the basis of our relational database (ABCA4Database). RESULTS.Sequence variability among all ABCA4-deposited entries was calculated and reported as Shannon entropy score at the residue level. The three-dimensional model of ABCA4 structure was used to locate the spatial distribution of the observed variable regions. Our predictions from structural in silico tools were able to accurately link the functional effects of mutations to phenotype. The development of the ABCA4Database gathers all the available genetic and structural information, yielding a global view of the molecular basis of some retinal diseases.CONCLUSIONS. ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations. Additionally, our ABCA4 predicted structure is a good starting point for the creation of a new data analysis model, appropriate for precision medicine, in order to develop a deeper knowledge network of the disease and to improve the management of patients.

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“…Looking at mutations in rpoB and katG, which leads to rifampicin and isoniazid resistance respectively, clear structural features were identified that correlated strongly with the resulting effectiveness of the drugs (MIC) 40 . A number of resistance mutations have also been observed across protein-protein interfaces, which raises the interesting hypothesis that similar to Mendelian disease mutations, those at interfaces might be prone to lead to disease and resistance because they have a lower fitness cost associated to them than those in the active site that completely disrupt activity 36,41,42 .…”

Section: Screening For Drug Resistance In Tuberculosismentioning

confidence: 99%

Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design

Albanaz

Rodrigues

Pires

et al. 2017

Expert Opinion on Drug Discovery

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Mutations introduce diversity into genomes, leading to selective changes and driving evolution. These changes have contributed to the emergence of many of the current major health concerns of the 21st century, from the development of genetic diseases and cancers to the rise and spread of drug resistance. The experimental systematic testing of all mutations in a system of interest is impractical and not cost-effective, which has created interest in the development of computational tools to understand the molecular consequences of mutations to aid and guide rational experimentation. Areas covered: Here, the authors discuss the recent development of computational methods to understand the effects of coding mutations to protein function and interactions, particularly in the context of the 3D structure of the protein. Expert opinion: While significant progress has been made in terms of innovative tools to understand and quantify the different range of effects in which a mutation or a set of mutations can give rise to a phenotype, a great gap still exists when integrating these predictions and drawing causality conclusions linking variants. This often requires a detailed understanding of the system being perturbed. However, as part of the drug development process it can be used preemptively in a similar fashion to pharmacokinetics predictions, to guide development of therapeutics to help guide the design and analysis of clinical trials, patient treatment and public health policy strategies.

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Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance

Cited by 35 publications

References 61 publications

Structural insights into the committed step of bacterial phospholipid biosynthesis

Structural insights into the committed step of bacterial phospholipid biosynthesis

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design

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