A5048787154- Protein Structure and Dynamics
- Viral Infections and Outbreaks Research
- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Lipid Membrane Structure and Behavior
- Antimicrobial Resistance in Staphylococcus
- Bacillus and Francisella bacterial research
- Influenza Virus Research Studies
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Antioxidant Activity and Oxidative Stress
- Retinoids in leukemia and cellular processes
- Viral Infections and Vectors
- Genomics and Phylogenetic Studies
- Cellular transport and secretion
- Sphingolipid Metabolism and Signaling
- Bacterial Identification and Susceptibility Testing
- Acute Myeloid Leukemia Research
- Click Chemistry and Applications
- Advancements in Transdermal Drug Delivery
- Child Therapy and Development
- Psychological Treatments and Assessments
- Toxin Mechanisms and Immunotoxins
- Microbial Natural Products and Biosynthesis
- Glycosylation and Glycoproteins Research
AbbVie (United States)
2022-2025
Washington University in St. Louis
2017-2022
University of Notre Dame
2013-2020
University of Florida
2009-2010
Protein stabilization is fundamental to enzyme function and evolution, yet understanding the determinants of a protein’s stability remains challenge. This largely due shortage atomically detailed models for ensemble relevant protein conformations their relative populations. For example, M182T substitution in TEM β-lactamase, an that confers antibiotic resistance bacteria, stabilizing but precise mechanism unclear. Here, we employ Markov state (MSMs) uncover how shifts distribution different...
Allosteric drugs, which bind to proteins in regions other than their main ligand-binding or active sites, make it possible target considered "undruggable" and develop new therapies that circumvent existing resistance. Despite growing interest allosteric drug discovery, rational design is limited by a lack of sufficient structural information about alternative binding sites proteins. Previously, we used Markov State Models (MSMs) identify such "cryptic pockets," here describe method for...
Abstract Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying exploiting remains challenging. Here, we apply a general pipeline cryptic to interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle lacks that...
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne 12%–30% case mortality rates and related to the Heartland (HRTV) identified in United States. Together, SFTSV HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens potential global health impact. Here, we characterize amino-terminal cap-snatching endonuclease domain of polymerase (L) solve 2.4-Å X-ray crystal structure. While overall structure similar those other sNSV endonucleases, differences near C...
Significance A protein is a shape-shifter, but it currently unclear which of the many structures can adopt are relevant for its function. Here, we examine conformations that contain “cryptic” pocket (i.e., absent in ligand-free structures). Cryptic pockets have potential utility drug discovery efforts because they provide means to target “undruggable” proteins lacking known pockets) or enhance rather than inhibit In this study, use combination thiol-labeling and kinetic assays, NMR,...
To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit growth. Because bacteria rely on two-component systems to respond environmental changes, and because these are both highly conserved mediated by histidine kinases, inhibiting kinases may provide broad spectrum activity. The kinase ATP binding domain is with ATPase eukaryotic Hsp90 molecular chaperones. find a chemical scaffold compounds that target leveraged...
The transmembrane antibiotic sensor/signal transducer protein BlaR1 is part of a cohort proteins that confer β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) [Fisher, J. F., Meroueh, S. O., and Mobashery, (2005) Chem. Rev. 105, 395-424; Llarrull, L. I., Fisher, (2009) Antimicrob. Agents Chemother. 53, 4051-4063; Toth, M., Champion, M. (2011) Biol. 286, 38148-38158]. Specifically, regulates the inducible expression β-lactamases hydrolytically destroy antibiotics....
The long-chain fatty acid C24:5 is likely an endogenous ligand of the retinoid X receptor α in mouse hematopoietic cells.
In methicillin-resistant Staphylococcus aureus, β-lactam antibiotic resistance is mediated by the transmembrane protein BlaR1. The sensor domain BlaR(S) and L2 loop of BlaR1 are on membrane surface. We used NMR to investigate interactions between a water-soluble peptide from L2. This binds proximal acylation site as an amphipathic helix. Acylation penicillin G does not disrupt binding. These results suggest signal transduction mechanism whereby helix, partially embedded in membrane,...
Abstract Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying exploiting remains challenging. Here, we apply a general pipeline cryptic to interferon inhibitory domain (IID) of Ebola viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola’s replication cycle lacks that utility...
The functional mechanisms of multidomain proteins often exploit interdomain interactions, or "cross-talk." An example is human Pin1, an essential mitotic regulator consisting a Trp-Trp (WW) domain flexibly tethered to peptidyl-prolyl isomerase (PPIase) domain, resulting in interactions important for Pin1 function. Substrate binding the WW alters its transient contacts with PPIase via means that are only partially understood. Accordingly, we have investigated using NMR paramagnetic relaxation...
Increasing evidence shows that active sites of proteins have non-trivial conformational dynamics. These dynamics include site residues sampling different local conformations allow for multiple, and possibly novel, inhibitor binding poses. Yet, garner only marginal attention in most design efforts exert little influence on synthesis strategies. This is partly because requires a level atomic structural detail frequently missing current characterizations In particular, while the identity mobile...
Abstract Understanding the functional role of protein excited states has important implications in design and drug discovery. However, because these are difficult to find study, it is still unclear if simply result from thermal fluctuations generally detract function or can actually enhance function. To investigate this question, we consider β-lactamases particularly a subset containing cryptic pocket which forms under Ω-loop. Given known importance Ω-loop presence at least two homologs,...
Abstract The retinoids all-trans retinoic acid (ATRA) and bexarotene are active in acute myeloid leukemia (AML), but responses beyond promyelocytic (APL) have been more modest than APL responses. To determine whether chemical modification of might augment retinoid AML, we screened a series 38 derivatives for activity mouse MLL-AF9 cell line, which exhibits strong synergistic sensitivity to the combination ATRA bexarotene. We found that RXRA potency correlated with anti-leukemic only one...