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Disulfide Bond Engineering of Soluble ACE2 for Thermal Stability Enhancement.
Int J Mol Sci
September 2024
Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea.
Although the primary pandemic of SARS-CoV-2 is over, there are concerns about the resurgence of the next wave of related viruses, including a wide range of variant viruses. The soluble ACE2 (sACE2) inhibits the SARS-CoV-2 spike protein ACE2 interaction and has potential as a variant-independent therapeutic against SARS-CoV-2. Here, we introduce novel disulfide bonds in the wild-type sACE2-Fc by structure-guided mutagenesis, aiming to improve its stability.
View Article and Find Full Text PDFStructure-Guided Identification of Novel Aromatase Inhibitors Targeting Breast Carcinoma.
Chem Biodivers
November 2024
Department of Biomedical Engineering, SRM University, Delhi-NCR, Sonepat, Haryana, 131029, India.
Aromatase inhibitors play a critical therapeutic role in treating ER+ breast cancer, especially in postmenopausal women. However, their efficacy is often limited by resistance and severe side effects. Identifying new compounds that can disrupt aromatase enzyme function is essential.
View Article and Find Full Text PDFEngineering APOBEC3A deaminase for highly accurate and efficient base editing.
Nat Chem Biol
September 2024
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Cytosine base editors (CBEs) are effective tools for introducing C-to-T base conversions, but their clinical applications are limited by off-target and bystander effects. Through structure-guided engineering of human APOBEC3A (A3A) deaminase, we developed highly accurate A3A-CBE (haA3A-CBE) variants that efficiently generate C-to-T conversion with a narrow editing window and near-background level of DNA and RNA off-target activity, irrespective of methylation status and sequence context. The engineered deaminase domains are compatible with PAM-relaxed SpCas9-NG variant, enabling accurate correction of pathogenic mutations in homopolymeric cytosine sites through flexible positioning of the single-guide RNAs.
View Article and Find Full Text PDFStructure-guided discovery of aminopeptidase ERAP1 variants capable of processing antigens with novel PC anchor specificities.
Immunology
January 2024
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, Massachusetts, USA.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) belongs to the oxytocinase subfamily of M1 aminopeptidases (M1APs), which are a diverse family of metalloenzymes involved in a wide range of functions and have been implicated in various chronic and infectious diseases of humans. ERAP1 trims antigenic precursors into correct sizes (8-10 residues long) for Major Histocompatibility Complex (MHC) presentation, by a unique molecular ruler mechanism in which it makes concurrent bindings to substrate N- and C-termini. We have previously determined four crystal structures of ERAP1 C-terminal regulatory domain (termed ERAP1_C domain) in complex with peptide carboxyl (PC)-ends that carry various anchor residues, and identified a specificity subsite for recognizing the PC anchor side chain, denoted as the SC subsite to follow the conventional notations: S1 site for P1, S2 site for P2, and so forth.
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