Correlation between Charge Transport and Base Excision Repair in the MutY–DNA Glycosylase

Teo, Ruijie D.; Du, Xiaochen; Vera, Héctor Luis Torres; Migliore, Agostino; Beratan, David N.

doi:10.1021/acs.jpcb.0c08598

Cited by 3 publications

(3 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In support of these ideas, previous work has shown that the Fe-S cluster is more easily oxidized when MutY is bound to DNA indicating that alterations resulting from DNA binding impact the Fe–S cluster environment and properties ( 49 ). The mechanism for communication seems to work in both directions as different oxidation states of the cluster appear to be transmitted to the active site and influence adenine excision ( 50 ).…”

Section: Resultsmentioning

confidence: 99%

Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism

Demir

Russelburg

Lin

et al. 2023

Nucleic Acids Research

View full text Add to dashboard Cite

DNA glycosylase MutY plays a critical role in suppression of mutations resulted from oxidative damage, as highlighted by cancer-association of the human enzyme. MutY requires a highly conserved catalytic Asp residue for excision of adenines misinserted opposite 8-oxo-7,8-dihydroguanine (OG). A nearby Asn residue hydrogen bonds to the catalytic Asp in structures of MutY and its mutation to Ser is an inherited variant in human MUTYH associated with colorectal cancer. We captured structural snapshots of N146S Geobacillus stearothermophilus MutY bound to DNA containing a substrate, a transition state analog and enzyme-catalyzed abasic site products to provide insight into the base excision mechanism of MutY and the role of Asn. Surprisingly, despite the ability of N146S to excise adenine and purine (P) in vitro, albeit at slow rates, N146S-OG:P complex showed a calcium coordinated to the purine base altering its conformation to inhibit hydrolysis. We obtained crystal structures of N146S Gs MutY bound to its abasic site product by removing the calcium from crystals of N146S-OG:P complex to initiate catalysis in crystallo or by crystallization in the absence of calcium. The product structures of N146S feature enzyme-generated β-anomer abasic sites that support a retaining mechanism for MutY-catalyzed base excision.

show abstract

Section: Resultsmentioning

confidence: 99%

Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism

Demir

Russelburg

Lin

et al. 2023

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…The iron–sulfur cluster is an ancient and essential protein cofactor with various compositions and structures , and is widely distributed in bacteria , and mammals, , indicative of conserved biological evolution to some extent . The three major iron–sulfur clusters in organisms, Isc (iron–sulfur cluster), Nif (nitrogen fixation), and Suf (sulfur utilization factor), play significant roles on nucleic acid replication and repair, nitrogen fixation, and bacterial sulfur depletion processes. , Iron–sulfur clusters in mammals generally exist as [2Fe2S], [4Fe4S], and [3Fe4S] − and participate in various physiological processes such as mitochondrial respiration, DNA replication, , and repair, ,, via the ligand binding of Fe atoms with cysteine/histidine residues. The [4Fe4S] cluster generally serves itself as an electron transfer switch involved in the redox process of DNA replication and repair.…”

Section: Introductionmentioning

confidence: 99%

Functionalization of Mesoporous Silica with a G-A-Mismatched dsDNA Chain for Efficient Identification and Selective Capturing of the MutY Protein

Sun

Wang

Chen

2023

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

MUTYH adenine DNA glycosylase and its homologous protein (collectively MutY) are typical DNA glycosylases with a [4Fe4S] cluster and a helix–hairpin–helix (HhH) motif in its structure. In the present work, the binding behaviors of the MutY protein to dsDNA containing different base mismatches were investigated. The type and distribution of base mismatch in the dsDNA chain were found to influence the DNA–protein binding interaction greatly. The [4Fe4S] cluster of the MutY protein is able to identify a G-A mismatch in the dsDNA chain specifically by monitoring the anomalies of charge transport in the dsDNA chain, allowing the entrance of the identified dsDNA chain into the internal cavity of the MutY protein and the strong DNA–protein binding at the HhH motif of the protein through multiple H-bonds. The dsDNA chain with a centrally located G-A mismatch is thus functionalized on mesoporous silica (MSN) via amination reaction, and the obtained dsDNA(G-A)@MSN is used as a powerful sorbent for the selective capturing of the MutY protein from complex samples. By using 0.5% NH3·H2O (m/v) as a stripping reagent, efficient isolation of the MutY protein from different cell lines and bacteria is achieved and the recovered MutY protein is demonstrated to maintain favorable DNA adenine glycosylase activity.

show abstract

“…The abundance and ubiquity of metalloproteins have attracted much scientific endeavors to understand the relationships between protein structures and functions [4,5], and translate that understanding into real-life applications [6,7]. While traditional molecular modeling approaches, such as classical molecular dynamics [8,9] and quantum mechanics/molecular mechanics (QM/MM) methods [10], have often been used to study these objectives, the usage of machine learning models has grown in popularity over the last decade [11], as metalloproteins can now be studied in a computationally inexpensive manner at a systems level. By designing and optimizing models to learn patterns and distinctions from training and validation data sets, these machine learning models can eventually predict the properties and behaviors of any new inputs (i.e., test sets).…”

Section: Introductionmentioning

confidence: 99%

Machine Learning Approaches for Metalloproteins

Wang

Teo

2022

Molecules

Self Cite

View full text Add to dashboard Cite

Metalloproteins are a family of proteins characterized by metal ion binding, whereby the presence of these ions confers key catalytic and ligand-binding properties. Due to their ubiquity among biological systems, researchers have made immense efforts to predict the structural and functional roles of metalloproteins. Ultimately, having a comprehensive understanding of metalloproteins will lead to tangible applications, such as designing potent inhibitors in drug discovery. Recently, there has been an acceleration in the number of studies applying machine learning to predict metalloprotein properties, primarily driven by the advent of more sophisticated machine learning algorithms. This review covers how machine learning tools have consolidated and expanded our comprehension of various aspects of metalloproteins (structure, function, stability, ligand-binding interactions, and inhibitors). Future avenues of exploration are also discussed.

show abstract

Correlation between Charge Transport and Base Excision Repair in the MutY–DNA Glycosylase

Cited by 3 publications

References 48 publications

Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism

Structural snapshots of base excision by the cancer-associated variant MutY N146S reveal a retaining mechanism

Functionalization of Mesoporous Silica with a G-A-Mismatched dsDNA Chain for Efficient Identification and Selective Capturing of the MutY Protein

Machine Learning Approaches for Metalloproteins

Contact Info

Product

Resources

About