Structure of the sliding clamp from the fungal pathogen <i>Aspergillus fumigatus</i> (Afum<scp>PCNA</scp>) and interactions with Human p21

Marshall, A.C.; Kroker, Alice J.; Murray, Lauren A. M.; Gronthos, Kahlia; Rajapaksha, Harinda; Wegener, Kate L.; Bruning, John B.

doi:10.1111/febs.14035

Cited by 11 publications

(20 citation statements)

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“…There is a salt bridge formed by K110(NZ) of β13 with D143(OD2) of α2′. This salt bridge interaction is conserved among other known eukaryotic PCNA structures [11,32,61,62], perhaps, indicating its crucial role in PCNA trimer stability (Table S1). Additionally, in the core region, the buried surface is highly hydrophobic, which is formed around the Y114 of β9′, surrounded by I78, I79 and A82 of α3, I116 of β9′, L151 and L154 of α3′ and I175 and V180 of β9′ (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…At the subunit interface, the hydrogen-bonding partners and patterns are relatively well conserved among S. cerevisiae, D. melanogaster, H. sapiens, A. fumigatus and A. thaliana PCNAs. A difference observed at the subunit interface of PCNA from the different species is for N153 in CaPCNA which is substituted by Q153 (ScPCNA and DmPCNA), A153 (AfPCNA), H153 (Hs/AfPCNA) and S153 (AtPCNA) [11,32,62,70]. Another variation in the interaction observed in CaPCNA is at S81 that contacts the K146(NZ) of the adjacent subunit (Fig.…”

Section: Comparison Of Capcna With Other Pcna Structuresmentioning

confidence: 99%

“…Besides, the emergence of multidrug resistance species warrants the identification of new fungal drug targets and more potent therapeutics. Among pathogenic fungi, the structure of PCNA from Aspergillus fumigatus (AfPCNA) alone has been reported [32]. However, no studies have focused on the structural characterisation of PCNA from other pathogenic fungi, including C. albicans, and targeting this essential protein for antifungal drug development.…”

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confidence: 99%

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Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

et al. 2021

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An assembly of multiprotein complexes achieves chromosomal DNA replication at the replication fork. In eukaryotes, proliferating cell nuclear antigen (PCNA) plays a vital role in the assembly of multiprotein complexes at the replication fork and is essential for cell viability. PCNA from several organisms, including Saccharomyces cerevisiae, has been structurally characterised. However, the structural analyses of PCNA from fungal pathogens are limited. Recently, we have reported that PCNA from the opportunistic fungal pathogen Candida albicans complements the essential functions of ScPCNA in S. cerevisiae. Still, it only partially rescues the loss of ScPCNA when the yeast cells are under genotoxic stress. To understand this further, herein, we have determined the crystal structure of CaPCNA and compared that with the existing structures of other fungal and human PCNA. Our comparative structural and in‐solution small‐angle X‐ray scattering (SAXS) analyses reveal that CaPCNA forms a stable homotrimer, both in crystal and in solution. It displays noticeable structural alterations in the oligomerisation interface, P‐loop and hydrophobic pocket regions, suggesting its differential function in a heterologous system and avenues for developing specific therapeutics. Databases The PDB and SASBDB accession codes for CaPCNA are https://doi.org/10.2210/pdb7BUP/pdb and SASDHQ9, respectively.

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Section: Resultsmentioning

confidence: 88%

Section: Comparison Of Capcna With Other Pcna Structuresmentioning

confidence: 99%

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confidence: 99%

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Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

et al. 2021

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“…Crystals were mounted on cryoloops, cryoprotected using paratone-N, and flash cooled in liquid nitrogen (29)(30)(31). Data was collected at 100 K using the MX1 beamline at the Australian Synchrotron (Clayton, Vic).…”

Section: Protein-peptide Co-crystallisation Experimentsmentioning

confidence: 99%

Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA

Horsfall

Vandborg

Kowalczyk

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…This class of enzyme belongs to the d -isomer–specific 2-hydroxyacid dehydrogenase (2KDH) superfamily, which catalyzes the reversible reduction of 2-oxoacids to the d -isomers of the respective 2-hydroxyacids. It should be noted that IA has a dextrorotatory ( d ) C2, although it is named as “ l -idonic acid.” Most recently, a similar 2-keto- l -gulonate reductase, catalyzing the reversible reduction of 2KLG to IA, was identified from the bacteria Ketogulonicigenium vulgare (30) and the filamentous fungus Aspergillus niger (31), suggesting that this enzyme may be ubiquitous in all living microorganisms. However, no such enzyme has been reported in plants.…”

Section: Introductionmentioning

confidence: 99%

An aldo-keto reductase with 2-keto-l-gulonate reductase activity functions in l-tartaric acid biosynthesis from vitamin C in Vitis vinifera

Jia

Burbidge

Sweetman

et al. 2019

Journal of Biological Chemistry

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Tartaric acid has high economic value as an antioxidant and flavorant in food and wine industries. l-Tartaric acid biosynthesis in wine grape (Vitis vinifera) uses ascorbic acid (vitamin C) as precursor, representing an unusual metabolic fate for ascorbic acid degradation. Reduction of the ascorbate breakdown product 2-keto-l-gulonic acid to l-idonic acid constitutes a critical step in this l-tartaric acid biosynthetic pathway. However, the underlying enzymatic mechanisms remain obscure. Here, we identified a V. vinifera aldo-keto reductase, Vv2KGR, with 2-keto-l-gulonic acid reductase activity. Vv2KGR belongs to the d-isomer–specific 2-hydroxyacid dehydrogenase superfamily and displayed the highest similarity to the hydroxyl pyruvate reductase isoform 2 in Arabidopsis thaliana. Enzymatic analyses revealed that Vv2KGR efficiently reduces 2-keto-l-gulonic acid to l-idonic acid and uses NADPH as preferred coenzyme. Moreover, Vv2KGR exhibited broad substrate specificity toward glyoxylate, pyruvate, and hydroxypyruvate, having the highest catalytic efficiency for glyoxylate. We further determined the X-ray crystal structure of Vv2KGR at 1.58 Å resolution. Comparison of the Vv2KGR structure with those of d-isomer–specific 2-hydroxyacid dehydrogenases from animals and microorganisms revealed several unique structural features of this plant hydroxyl pyruvate reductase. Substrate structural analysis indicated that Vv2KGR uses two modes (A and B) to bind different substrates. 2-Keto-l-gulonic acid displayed the lowest predicted free-energy binding to Vv2KGR among all docked substrates. Hence, we propose that Vv2KGR functions in l-tartaric acid biosynthesis. To the best of our knowledge, this is the first report of a d-isomer–specific 2-hydroxyacid dehydrogenase that reduces 2-keto-l-gulonic acid to l-idonic acid in plants.

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Structure of the sliding clamp from the fungal pathogen Aspergillus fumigatus (AfumPCNA) and interactions with Human p21

Abstract: The atomic coordinates and structure factors for the Aspergillus fumigatus sliding clamp can be found in the RCSB Protein Data Bank (http://www.rcsb.org) under the accession code 5TUP.

Cited by 11 publications

References 77 publications

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

Unlocking the PIP-box: A peptide library reveals interactions that drive high-affinity binding to human PCNA

An aldo-keto reductase with 2-keto-l-gulonate reductase activity functions in l-tartaric acid biosynthesis from vitamin C in Vitis vinifera

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