Stephen Orlicky

The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4

Chetan K. Chana, Ines Ben Makhlouf, Jaeyoun Kim, Annie Yu et autres

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Molecular basis for the activation of Aurora A and Plk1 kinases during mitotic entry

Anaïs Pillan, Philippine Ormancey, Celia Ben Choug, Stephen Orlicky et autres

The evolutionarily conserved, intrinsically disordered protein Bora is critical for initiating the activation of mitotic kinases. Once phosphorylated at Ser112 by Cyclin A-Cdk1 kinase, phospho-Bora activates unphosphorylated Aurora A kinase (AURKA), directing it towards Polo-like kinase 1 (Plk1), thus promoting Cyclin B-Cdk1 …

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Design of a Targeted Covalent Probe to Interrogate the DNA Polymerase Activity of Polθ

Monica Bubenik, P. Mäder, Stephen Orlicky, Alexander L. Perryman et autres

Human DNA polymerase θ (Polθ) is essential for microhomology-mediated end-joining (MMEJ) and represents a therapeutic vulnerability in homologous recombination (HR)-deficient cancers. Although reversible inhibitors of Polθ have advanced into clinical development, covalent chemical probes remain unexplored. Analysis of a previously described structure …

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Author Correction: A substrate binding model for the KEOPS tRNA modifying complex

Jonah Beenstock, Samara Mishelle Ona, Jennifer Porat, Stephen Orlicky et autres

In the version of the article initially published, there was a model building error in the reported crystal structure of an isolated tRNA molecule (PDB 7KJU ) and the X-ray crystal structure of the same tRNA molecule bound to CGI121 (PDB 7KJT …

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FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation

Philip Barbulescu, Chetan K. Chana, Matthew K. Wong, Ines Ben Makhlouf et autres

A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair …

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A Novel Confocal Scanning Protein–Protein Interaction Assay (PPI-CONA) Reveals Exceptional Selectivity and Specificity of CC0651, a Small Molecule Binding Enhancer of the Weak Interaction between the E2 Ubiquitin-Conjugating Enzyme CDC34A and Ubiquitin

Joanna Koszela, Nhan T. Pham, Steven Shave, Daniel J. St‐Cyr et autres

Protein-protein interactions (PPIs) are some of the most challenging target classes in drug discovery. Highly sensitive detection techniques are required for the identification of chemical modulators of PPIs. Here, we introduce PPI confocal nanoscanning (PPI-CONA), a miniaturized, microbead based high-resolution fluorescence imaging …

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Engineered antigen‐binding fragments for enhanced crystallization of antibody:antigen complexes

Heather Bruce, A.U. Singer, E.V. Filippova, Levi L. Blazer et autres

The atomic-resolution structural information that X-ray crystallography can provide on the binding interface between a Fab and its cognate antigen is highly valuable for understanding the mechanism of interaction. However, many Fab:antigen complexes are recalcitrant to crystallization, making the endeavor a considerable …

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Engineered Antigen-Binding Fragments for Enhanced Crystallisation of Antibody:Antigen Complexes

Heather A. Bruce, A.U. Singer, E.V. Filippova, Levi L. Blazer et autres

ABSTRACT The atomic-resolution structural information that X-ray crystallography can provide on the binding interface between a Fab and its cognate antigen is highly valuable for understanding the mechanism of interaction. However, many Fab:antigen complexes are recalcitrant to crystallisation, making the endeavour a …

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SCFFBXW7 regulates G2‐M progression through control of CCNL1 ubiquitination

Siobhan O’Brien, Susan Kelso, Zachary Steinhart, Stephen Orlicky et autres

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SCF FBXW7 regulates G2-M progression through control of CCNL1 ubiquitination

Siobhan O’Brien, Susan Kelso, Zachary Steinhart, Stephen Orlicky et autres

Abstract FBXW7 , which encodes a substrate specific receptor of an SCF E3 ligase complex, is a frequently mutated human tumor suppressor gene known to regulate the post-translational stability of various proteins involved in cellular proliferation. Here, using genome-wide CRISPR screens we …

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Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306

Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu et autres

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported …

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Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu et autres

PKMYT1 is an important regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been …

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