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• W3092221921 abstract "Abstract Impaired enzymatic activity in D-amino acid oxidase (DAAO) caused by missense mutations has been shown to trigger amyotrophic lateral sclerosis (ALS) through an abnormal accumulation of D-serine in the spinal cord. While loss of enzymatic functions of certain ALS-causing DAAO variants have been studied before, a detailed understanding of structure-dynamics-function relationship of the rare DAAO variants has not been investigated hitherto. To address this, we carried out a comprehensive study of all the reported rare DAAO variants. By employing a spectrum of bioinformatics analyses along with extensive structural dynamics simulations, we show that certain rare variants disrupted key interactions with the active site and decreased the conformational flexibility of active site loop comprising residues 216–228, which is essential for substrate binding and product release. Moreover, these variants lost crucial interactions with the cofactor flavin-adenine-dinucleotide, resulting in weaker binding affinity. A detailed inspection revealed that these variants exhibited such characteristics due to the abrogation of specific salt bridges. Taken together, our study provides a gateway into the structural-dynamic features of the rare DAAO variants and highlights the importance of informatics-based integrated analyses in the screening and prioritization of variants a priori to the clinical-functional characterization." @default.
• W3092221921 created "2020-10-15" @default.
• W3092221921 creator A5044307373 @default.
• W3092221921 creator A5080510069 @default.
• W3092221921 date "2020-10-13" @default.
• W3092221921 modified "2023-10-14" @default.
• W3092221921 title "Mechanistic insights into the loss-of-function mechanisms of rare human D-amino acid oxidase variants implicated in amyotrophic lateral sclerosis" @default.
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• W3092221921 doi "https://doi.org/10.1038/s41598-020-74048-2" @default.
• W3092221921 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7555490" @default.
• W3092221921 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33051492" @default.
• W3092221921 hasPublicationYear "2020" @default.
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