A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase
DNA-mimicking proteins encoded by viruses can modulate processes such as innate cellular immunity. An example is Ung-family uracil-DNA glycosylase inhibition, which prevents Ung-mediated degradation via the stoichiometric protein blockade of the Ung DNA-binding cleft. This is significant where uraci...
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MDPI AG
2023-06-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/6/1348 |
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| author | Wael Muselmani Naail Kashif-Khan Claire Bagnéris Rosalia Santangelo Mark A. Williams Renos Savva |
| author_facet | Wael Muselmani Naail Kashif-Khan Claire Bagnéris Rosalia Santangelo Mark A. Williams Renos Savva |
| author_sort | Wael Muselmani |
| collection | DOAJ |
| description | DNA-mimicking proteins encoded by viruses can modulate processes such as innate cellular immunity. An example is Ung-family uracil-DNA glycosylase inhibition, which prevents Ung-mediated degradation via the stoichiometric protein blockade of the Ung DNA-binding cleft. This is significant where uracil-DNA is a key determinant in the replication and distribution of virus genomes. Unrelated protein folds support a common physicochemical spatial strategy for Ung inhibition, characterised by pronounced sequence plasticity within the diverse fold families. That, and the fact that relatively few template sequences are biochemically verified to encode Ung inhibitor proteins, presents a barrier to the straightforward identification of Ung inhibitors in genomic sequences. In this study, distant homologs of known Ung inhibitors were characterised via structural biology and structure prediction methods. A recombinant cellular survival assay and in vitro biochemical assay were used to screen distant variants and mutants to further explore tolerated sequence plasticity in motifs supporting Ung inhibition. The resulting validated sequence repertoire defines an expanded set of heuristic sequence and biophysical signatures shared by known Ung inhibitor proteins. A computational search of genome database sequences and the results of recombinant tests of selected output sequences obtained are presented here. |
| first_indexed | 2024-03-11T01:50:25Z |
| format | Article |
| id | doaj.art-cf4d2c0ce721433cb598002bba7b436e |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-11T01:50:25Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-cf4d2c0ce721433cb598002bba7b436e2023-11-18T13:02:32ZengMDPI AGViruses1999-49152023-06-01156134810.3390/v15061348A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA GlycosylaseWael Muselmani0Naail Kashif-Khan1Claire Bagnéris2Rosalia Santangelo3Mark A. Williams4Renos Savva5Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKInstitute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London WC1E 7HX, UKDNA-mimicking proteins encoded by viruses can modulate processes such as innate cellular immunity. An example is Ung-family uracil-DNA glycosylase inhibition, which prevents Ung-mediated degradation via the stoichiometric protein blockade of the Ung DNA-binding cleft. This is significant where uracil-DNA is a key determinant in the replication and distribution of virus genomes. Unrelated protein folds support a common physicochemical spatial strategy for Ung inhibition, characterised by pronounced sequence plasticity within the diverse fold families. That, and the fact that relatively few template sequences are biochemically verified to encode Ung inhibitor proteins, presents a barrier to the straightforward identification of Ung inhibitors in genomic sequences. In this study, distant homologs of known Ung inhibitors were characterised via structural biology and structure prediction methods. A recombinant cellular survival assay and in vitro biochemical assay were used to screen distant variants and mutants to further explore tolerated sequence plasticity in motifs supporting Ung inhibition. The resulting validated sequence repertoire defines an expanded set of heuristic sequence and biophysical signatures shared by known Ung inhibitor proteins. A computational search of genome database sequences and the results of recombinant tests of selected output sequences obtained are presented here.https://www.mdpi.com/1999-4915/15/6/1348virusbacteriophageMRSASCCmecuracil-DNA glycosylaseUgi |
| spellingShingle | Wael Muselmani Naail Kashif-Khan Claire Bagnéris Rosalia Santangelo Mark A. Williams Renos Savva A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase Viruses virus bacteriophage MRSA SCCmec uracil-DNA glycosylase Ugi |
| title | A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase |
| title_full | A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase |
| title_fullStr | A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase |
| title_full_unstemmed | A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase |
| title_short | A Multimodal Approach towards Genomic Identification of Protein Inhibitors of Uracil-DNA Glycosylase |
| title_sort | multimodal approach towards genomic identification of protein inhibitors of uracil dna glycosylase |
| topic | virus bacteriophage MRSA SCCmec uracil-DNA glycosylase Ugi |
| url | https://www.mdpi.com/1999-4915/15/6/1348 |
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