A5087019182- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Vascular Malformations Diagnosis and Treatment
- PI3K/AKT/mTOR signaling in cancer
- Retinal and Macular Surgery
- Retinal Development and Disorders
- Metabolomics and Mass Spectrometry Studies
- Mass Spectrometry Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Intracranial Aneurysms: Treatment and Complications
- Radiopharmaceutical Chemistry and Applications
- Endoplasmic Reticulum Stress and Disease
- Viral-associated cancers and disorders
- Cellular transport and secretion
Harvard University
2024-2025
Dana-Farber Cancer Institute
2023-2025
University of Massachusetts Amherst
2022
Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack selective chemical probes impedes pharmacologic interrogation this important gene family. DUBs engage their cognate ligands through a myriad interactions. We embrace structural complexity tailor diversification strategy for DUB-focused covalent library. Pairing our library with activity-based profiling as high-density...
Ubiquitin-specific protease 7 (USP7) is a deubiquitylase essential for cell homeostasis, DNA repair, and regulation of both tumor suppressors oncogenes. Inactivating USP7 mutations have been associated with Hao-Fountain Syndrome (HAFOUS), rare neurodevelopmental disorder. Although range inhibitors developed over the last decade, in context HAFOUS as well oncogene regulation, activators may represent more relevant approach. To address this challenge, we report discovery characterization...
Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the de-ubiquitinating enzyme USP7 (Ubiquitin Specific Protease 7). Due to novelty of disease and its poorly understood molecular mechanisms, treatments for are currently lacking. This study examines effects 11 patient-derived variants located within catalytic domain USP7, focusing on their impact enzyme's activity, thermodynamic stability, substrate recognition. Our findings reveal spectrum functional...
VCP/p97 regulates a wide range of cellular processes, including post-mitotic Golgi reassembly. In this context, VCP is assisted by p47, an adapter protein, and VCPIP1, deubiquitinase (DUB). However, how they organize into functionally competent complex promote reassembly remains unknown. Here, we use cryo-EM to characterize VCP-VCPIP1 VCP-VCPIP1-p47 complexes. We show that VCPIP1 engages through two interfaces: one involving the N-domain UBX domain other D2 domains region refer as VCPID. The...
Target-based screening of covalent fragment libraries with mass spectrometry has emerged as a powerful strategy to identify chemical starting points for small molecule inhibitors or find new binding pockets on proteins interest. These span diverse space modest number compounds. Screening fragments against purified protein targets reduces the demands spectrometer respect absolute throughput, detection limit, and dynamic range. Given these relaxed analytical requirements, we sought develop an...