Author Correction: Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine

Kavanagh, Madeline E.; Horning, Benjamin D.; Khattri, Roli; Roy, Nilotpal; Lu, Justine P; Whitby, Landon R.; Ye, Elva; Brannon, Jaclyn C; Parker, Albert E.; Chick, Joel M.; Eissler, Christie L.; Wong, Ashley J; Rodriguez, Joe L; Rodiles, Socorro; Masuda, Kim; Teijaro, John R.; Simón, Gabriel; Patricelli, Matthew P.; Cravatt, Benjamin F.

doi:10.1038/s41589-022-01181-6

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“…Similar to the target‐centric approach, the ligand‐centric approach also requires chemical optimization to improve the potency and selectivity of the fragment hits for the target of interest. In a recent application of ligand‐centric FBDD, Cravatt and coworkers successfully developed novel allosteric modulators of the Janus tyrosine kinase 1 (JAK1) with high potency and unprecedented isoform selectivity within the JAK family, which involved initial screening of a covalent fragment library against the human T‐cell proteome for discovering the fragment hits of JAK1 [48] …”

Section: Approaches For Discovering Covalent Ligandsmentioning

confidence: 99%

“…In a recent application of ligand-centric FBDD, Cravatt and coworkers successfully developed novel allosteric modulators of the Janus tyrosine kinase 1 (JAK1) with high potency and unprecedented isoform selectivity within the JAK family, which involved initial screening of a covalent fragment library against the human T-cell proteome for discovering the fragment hits of JAK1. [48] In this review, we present two case studies that involved the application of either the target-centric or the ligand-centric method toward covalent ligand discovery in our laboratory. Employing the target-centric method, we rapidly identified highly potent and specific inhibitors for a receptor tyrosine kinase EphB3.…”

Section: Approaches For Discovering Covalent Ligandsmentioning

confidence: 99%

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Identification of Covalent Ligands – from Single Targets to Whole Proteome

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Ekanayake

Zhang

2023

Israel Journal of Chemistry

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There has been a surge of interest and efforts in the discovery of covalent ligands for diverse proteins as tool compounds or therapeutic candidates in recent years. We present two studies that involve applications of a targetcentric approach and a ligand-centric approach toward covalent ligand discovery. By targeting a rare cysteine residue in a receptor tyrosine kinase EphB3, we were able to rapidly identify potent inhibitors of EphB3 with extraordinary proteomic selectivity supported by activity-based probe profiling. While characterizing an activity-based probe intended for EphB3 using ABPP, we made a surprising discovery that its primary cellular target was a catalytic subunit of V-ATPase through its covalent engagement with a cryptic pocket on V-ATPase. These two approaches will be increasingly used in combination to develop covalent ligands with high potency and yield comprehensive target profiles to accelerate the rate of therapeutic discovery in the future.

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Section: Approaches For Discovering Covalent Ligandsmentioning

confidence: 99%

Section: Approaches For Discovering Covalent Ligandsmentioning

confidence: 99%

Identification of Covalent Ligands – from Single Targets to Whole Proteome

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Ekanayake

Zhang

2023

Israel Journal of Chemistry

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Understanding Cysteine Chemistry Using Conventional and Serial X-ray Protein Crystallography

Smith

Wilson

2022

Crystals

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Proteins that use cysteine residues for catalysis or regulation are widely distributed and intensively studied, with many biomedically important examples. Enzymes where cysteine is a catalytic nucleophile typically generate covalent catalytic intermediates whose structures are important for understanding mechanism and for designing targeted inhibitors. The formation of catalytic intermediates can change enzyme conformational dynamics, sometimes activating protein motions that are important for catalytic turnover. However, these transiently populated intermediate species have been challenging to structurally characterize using traditional crystallographic approaches. This review describes the use and promise of new time-resolved serial crystallographic methods to study cysteine-dependent enzymes, with a focus on the main (Mpro) and papain-like (PLpro) cysteine proteases of SARS-CoV-2, as well as on other examples. We review features of cysteine chemistry that are relevant for the design and execution of time-resolved serial crystallography experiments. In addition, we discuss emerging X-ray techniques, such as time-resolved sulfur X-ray spectroscopy, that may be able to detect changes in sulfur charge states and covalency during catalysis or regulatory modification. In summary, cysteine-dependent enzymes have features that make them especially attractive targets for new time-resolved serial crystallography approaches, which can reveal both changes to enzyme structures and dynamics during catalysis in crystalline samples.

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Author Correction: Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine

Cited by 2 publications

References 0 publications

Identification of Covalent Ligands – from Single Targets to Whole Proteome

Identification of Covalent Ligands – from Single Targets to Whole Proteome

Understanding Cysteine Chemistry Using Conventional and Serial X-ray Protein Crystallography

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