A5088440311- HIV Research and Treatment
- HIV/AIDS drug development and treatment
- Protein Structure and Dynamics
- HIV/AIDS Research and Interventions
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Parasitic Infections and Diagnostics
- Protein Degradation and Inhibitors
- Lipid Membrane Structure and Behavior
- Multiple Myeloma Research and Treatments
- Animal Disease Management and Epidemiology
- Enzyme function and inhibition
- Biochemical and Structural Characterization
- Antimicrobial Peptides and Activities
- Prion Diseases and Protein Misfolding
- Glycosylation and Glycoproteins Research
- T-cell and Retrovirus Studies
- Hepatitis C virus research
- Protein Tyrosine Phosphatases
- vaccines and immunoinformatics approaches
- Cancer-related gene regulation
- Chronic Myeloid Leukemia Treatments
- Vector-Borne Animal Diseases
- Cell death mechanisms and regulation
University of Pittsburgh
2012-2024
Albert Einstein College of Medicine
2009
Université de Montréal
1997
Hematopoietic cell kinase (Hck) is a member of the Src family and promising drug target in myeloid leukemias. Here, we report crystal structure human Hck complex with pyrrolopyrimidine inhibitor A-419259, determined at resolution 1.8 Å. This reveals complete active site presence including αC-helix, DFG motif, activation loop. A-419259 binds ATP-site induces an overall closed conformation regulatory SH3 SH2 domains bound intramolecularly to their respective internal ligands. stabilizes...
Most mammalian cell types depend on multiple Src family kinases (SFKs) to regulate diverse signaling pathways. Strict control of SFK activity is essential for normal cellular function, and loss kinase regulation contributes several forms cancer other diseases. Previous x-ray crystal structures the SFKs c-Src Hck revealed that intramolecular association their homology (SH) 3 domains SH2 linker regions has a key role in down-regulation activity. However, amino acid sequence represents...
It has been clearly established that the budding of human immunodeficiency virus (HIV-1), a lentivirus, occurs specifically through basolateral membrane in polarized epithelial cells. More recently, signal was assigned to tyrosine-based motif located intracytoplasmic domain envelope glycoprotein, as previously observed on various other viral and cellular proteins. In present study, expression T-cell leukemia type 1 (HTLV-1) or Moloney murine glycoproteins used for trans-complementation an...
HIV-1 Nef is a viral accessory protein critical for AIDS progression. lacks intrinsic catalytic activity and binds multiple host cell signaling proteins, including Hck other Src-family tyrosine kinases. binding induces constitutive activation that may contribute to HIV pathogenesis by promoting infectivity, replication downregulation of cell-surface MHC-I molecules. In this study, we developed yeast-based phenotypic screen identify small molecules inhibit the Nef-Hck complex.Nef-Hck...
HIV-1 Nef is an attractive target for antiretroviral drug discovery because of its role in promoting infectivity, replication, and host immune system avoidance. Here, we applied a screening strategy which recombinant protein was coupled to activation the Src-family tyrosine kinase Hck, enhances life cycle macrophages. stimulates Hck activity
Nef is an HIV-1 accessory protein essential for viral replication and AIDS progression. interacts with a multitude of host cell signaling partners, including members the Src kinase family. preferentially activates Hck, Src-family (SFK) strongly expressed in macrophages other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified series inhibitors that inhibit Hck presence Nef. These compounds also block Nef-dependent replication, validating Nef-SFK pathway as...
The Nef protein produced by the viruses HIV-1 and SIV drives efficient viral replication partially inducing constitutive activation of host cell tyrosine kinases, including members Src Tec families. Here, we uncovered mechanism which both enhanced activity family kinase Btk in vitro cells. A mutant that could not bind to SH3 domain kinases activated same extent as did wild-type Nef, demonstrating distinct mechanisms. SH3-SH2 region formed a homodimer requiring CD loop SH2 domain, was...
The HIV-1 Nef accessory protein is essential for viral pathogenicity and AIDS progression. forms complexes with multiple host cell factors to facilitate replication promote immune escape of HIV-infected cells. Previous X-ray crystal structures demonstrate that homodimers, the orientation which are influenced by binding partners. In cell-based fluorescence complementation assays, homodimers at plasma membrane. However, recombinant proteins often exist as monomers in solution, suggesting...
SUMMARY The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo where it promotes immune escape of HIV-infected cells and persistence. While these features identify as an attractive antiretroviral drug target, lacks enzymatic activity active site, complicating development occupancy-based drugs. Here we describe proteolysis targeting chimeras (PROTACs) for targeted degradation Nef. Nef-binding compounds, based on a previously reported hydroxypyrazole core, were coupled...
Abstract The Src family of non-receptor protein-tyrosine kinases (SFKs) plays a crucial role in cancer progression by affecting multiple signaling pathways linked to tumor cell adhesion, invasion and survival. Recent work from our group others has shown that individual Src-family members may have unique some cases opposing roles the regulation growth differentiation. Discovery development SFK isoform-selective inhibitors agonists is therefore essential for most effective therapeutic...