A5057970267- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Photosynthetic Processes and Mechanisms
- Eosinophilic Disorders and Syndromes
- Fungal Plant Pathogen Control
- Photoreceptor and optogenetics research
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Microtubule and mitosis dynamics
- Plant and Biological Electrophysiology Studies
- Algal biology and biofuel production
- Microbial Metabolic Engineering and Bioproduction
- Biochemical and Molecular Research
- Cellular transport and secretion
- Protein Kinase Regulation and GTPase Signaling
- Immunodeficiency and Autoimmune Disorders
- Advanced NMR Techniques and Applications
- Multiple Myeloma Research and Treatments
- Click Chemistry and Applications
- Seaweed-derived Bioactive Compounds
- Protein Tyrosine Phosphatases
- Cancer-related gene regulation
- Light effects on plants
Biogen (United States)
2021-2024
Brandeis University
2014-2023
Howard Hughes Medical Institute
2015-2023
High Throughput Biology (United States)
2022
With early life likely to have existed in a hot environment, enzymes had cope with an inherent drop catalytic speed caused by lowered temperature. Here we characterize the molecular mechanisms underlying thermoadaptation of enzyme catalysis adenylate kinase using ancestral sequence reconstruction spanning 3 billion years evolution. We show that evolution solved enzyme's key kinetic obstacle-how maintain on cooler Earth-by exploiting transition-state heat capacity. Tracing activity and...
Evolution of dynamics affects function The drug Gleevac inhibits Abl kinases and is used to treat multiple cancers. closely related Src also play a role in cancer but are not inhibited effectively by Gleevac. Nevertheless, Gleevac-bound structures nearly identical. Based on this structural information protein sequence data, Wilson et al. reconstructed the common ancestor Abl. Mutations that affected conformational caused affinity be gained evolutionary trajectory toward lost Src. Science ,...
Abstract Circadian rhythms play an essential part in many biological processes, and only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator 1 . The evolutionary history of the Kai indicates that KaiC is oldest member central component clock 2 Subsequent additions KaiB KaiA regulate phosphorylation state for time synchronization. canonical KaiABC system cyanobacteria well understood 3–6 , but little known about more ancient systems possess...
Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity consequent adverse effects drugs targeting ATP binding site. Here we introduce an approach controlling kinase activity by using monobodies that bind highly specific regulatory allosteric pocket oncoprotein Aurora (AurA) kinase, thereby offering potential for more modulators. Strikingly, identify a series acting...
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), nonreceptor member of the TEC family kinases, involved in regulation, migration, functional activation B cells myeloid periphery central nervous system (CNS), cell types which are deemed to contributing progression MS patients. Herein, we describe discovery BIIB129 (25), structurally distinct...
Significance One obstacle for the prolonged success of wonder drug imatinib in leukemia has been emergence resistance mutations within Abl kinase domain. Here, we elucidate molecular mechanism three major patients treated with imatinib. Unpredictably, single-site act via a cumulative effect an only modest decrease affinity, combined increase enzyme activity and altered substrate affinity/cooperativity. Strikingly, this combination indeed leads to at least order-of-magnitude higher IC 50...
Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In early stage MS, inflammation primary driver disease progression. There remains an unmet need develop high efficacy therapies with superior safety profiles prevent processes Herein, we describe discovery BIIB091, structurally distinct orthosteric ATP competitive, reversible inhibitor...
Abstract Circadian rhythms play an essential role in many biological processes and surprisingly only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator. The evolutionary history of the Kai indicates that KaiC is oldest member central component clock, with subsequent additions KaiB KaiA regulate its phosphorylation state for time synchronization. canonical KaiABC system cyanobacteria well understood, but little known about more ancient systems...