Mischa Machius
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View article: Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor ΔFOSB
Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor ΔFOSB Open
ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors ar…
View article: Efficient <i>in vivo</i> pharmacological inhibition of ΔFOSB, an AP1 transcription factor, in brain
Efficient <i>in vivo</i> pharmacological inhibition of ΔFOSB, an AP1 transcription factor, in brain Open
ΔFOSB, an unusually stable member of the AP1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesias, and several other chronic neurologi…
View article: Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP1 Transcription Factor ΔFOSB
Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP1 Transcription Factor ΔFOSB Open
ΔFOSB, a member of the AP1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP1 transcription factors are …
View article: Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function
Designer molecules of the synaptic organizer MDGA1 reveal 3D conformational control of biological function Open
MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic developm…
View article: Chemically targeting the redox switch in AP1 transcription factor ΔFOSB
Chemically targeting the redox switch in AP1 transcription factor ΔFOSB Open
The AP1 transcription factor ΔFOSB, a splice variant of FOSB, accumulates in the brain in response to chronic insults such as exposure to drugs of abuse, depression, Alzheimer's disease and tardive dyskinesias, and mediates subsequent long…
View article: Structural Determinants of RGS-RhoGEF Signaling Critical to Entamoeba histolytica Pathogenesis
Structural Determinants of RGS-RhoGEF Signaling Critical to Entamoeba histolytica Pathogenesis Open
G-protein signaling pathways, as key components of physiologic responsiveness and timing, are frequent targets for pharmacologic intervention. Here, we identify an effector for heterotrimeric G-protein α subunit (EhGα1) signaling from Enta…
View article: Structural Determinants of Affinity Enhancement between GoLoco Motifs and G-Protein α Subunit Mutants
Structural Determinants of Affinity Enhancement between GoLoco Motifs and G-Protein α Subunit Mutants Open
GoLoco motif proteins bind to the inhibitory Gi subclass of G-protein α subunits and slow the release of bound GDP; this interaction is considered critical to asymmetric cell division and neuro-epithelium and epithelial progenitor differen…
View article: Computational de novo design of a four-helix bundle protein - DND-4HB
Computational de novo design of a four-helix bundle protein - DND-4HB Open
The de novo design of proteins is a rigorous test of our understanding of the key determinants of protein structure. The helix bundle is an interesting de novo design model system due to the diverse topologies that can be generated from a …
View article: Increasing Sequence Diversity with Flexible Backbone Protein Design: The Complete Redesign of a Protein Hydrophobic Core
Increasing Sequence Diversity with Flexible Backbone Protein Design: The Complete Redesign of a Protein Hydrophobic Core Open
Protein design tests our understanding of protein stability and structure. Successful design methods should allow the exploration of sequence space not found in nature. However, when redesigning naturally occurring protein structures most …
View article: Metal-Mediated Affinity and Orientation Specificity in a Computationally Designed Protein Homodimer
Metal-Mediated Affinity and Orientation Specificity in a Computationally Designed Protein Homodimer Open
Computationally designing protein-protein interactions with high affinity and desired orientation is a challenging task. Incorporating metal-binding sites at the target interface may be one approach for increasing affinity and specifying t…
View article: Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica
Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica Open
Heterotrimeric G-protein signaling pathways are vital components of physiology, and many are amenable to pharmacologic manipulation. Here, we identify functional heterotrimeric G-protein subunits in Entamoeba histolytica, the causative age…
View article: Computational Design of the Sequence and Structure of a Protein-Binding Peptide
Computational Design of the Sequence and Structure of a Protein-Binding Peptide Open
The de novo design of protein-binding peptides is challenging, because it requires identifying both a sequence and a backbone conformation favorable for binding. We used a computational strategy that iterates between structure and sequence…
View article: Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis
Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis Open
The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end…
View article: Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors
Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors Open
Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based …
View article: Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia
Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia Open
Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further a…
View article: TIR-only protein RBA1 recognizes a pathogen effector to regulate cell death in Arabidopsis
TIR-only protein RBA1 recognizes a pathogen effector to regulate cell death in Arabidopsis Open
Multicellular organisms must have complex immune systems to detect and defeat pathogens. Plants rely on nucleotide binding site leucine rich repeat (NLR) intracellular receptors to detect pathogens. For hundreds of years, plant breeders ha…
View article: Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme
Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme Open
Detailed structural comparisons of sperm-specific glyceraldehyde 3-phosphate dehydrogenase, spermatogenic (GAPDHS) and the somatic glyceraldehyde 3-phosphate dehydrogenase (GAPDH) isozyme should facilitate the identification of selective G…
View article: Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors
Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors Open
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In thi…
View article: Self-assembly of the bZIP transcription factor ΔFosB
Self-assembly of the bZIP transcription factor ΔFosB Open
ΔFosB is a highly stable transcription factor that accumulates in specific brain regions upon chronic exposure to drugs of abuse, stress, or seizures, and mediates lasting behavioral responses. ΔFosB reportedly heterodimerizes with JunD fo…
View article: Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors
Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors Open
Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reduc…
View article: Activator Protein-1: redox switch controlling structure and DNA-binding
Activator Protein-1: redox switch controlling structure and DNA-binding Open
The transcription factor, activator protein-1 (AP-1), binds to cognate DNA under redox control; yet, the underlying mechanism has remained enigmatic. A series of crystal structures of the AP-1 FosB/JunD bZIP domains reveal ordered DNA-bind…
View article: TIR-only protein RBA1 recognizes a pathogen effector to regulate cell death in<i>Arabidopsis</i>
TIR-only protein RBA1 recognizes a pathogen effector to regulate cell death in<i>Arabidopsis</i> Open
Significance Multicellular organisms must have complex immune systems to detect and defeat pathogens. Plants rely on nucleotide binding site leucine rich repeat (NLR) intracellular receptors to detect pathogens. For hundreds of years, plan…
View article: Discovery of Macrocyclic Pyrimidines as MerTK‐Specific Inhibitors
Discovery of Macrocyclic Pyrimidines as MerTK‐Specific Inhibitors Open
Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In thi…
View article: Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors
Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors Open
Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reduc…
View article: Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme
Structural analyses to identify selective inhibitors of glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme Open
This work was supported by grants from the National Institutes of Health (NIH), USA, including U01 HD060481 and cooperative agreement U54 HD35041 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Resear…