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Structural Basis for Gluten Intolerance in Celiac Sprue
TLDR
A 33-mer peptide was identified that has several characteristics suggesting it is the primary initiator of the inflammatory response to gluten in Celiac Sprue patients, and could be detoxified in in vitro and in vivo assays by exposure to a bacterial prolyl endopeptidase, suggesting a strategy for oral peptidase supplement therapy for CeliacSprue. Expand
Intestinal digestive resistance of immunodominant gliadin peptides.
TLDR
It is shown that these proline-glutamine-rich epitopes from alpha-gliadin are exceptionally resistant to enzymatic processing, and a possible enzyme therapy strategy for celiac sprue is suggested. Expand
FK506 Binding Protein 5 Shapes Stress Responsiveness: Modulation of Neuroendocrine Reactivity and Coping Behavior
TLDR
This study in mice and humans presents FKBP5 as a decisive factor for the physiological stress response, shaping neuroendocrine reactivity as well as coping behavior, lending strong support to the concept emerging from human studies of FK BP5 as important factor governing gene-environment interactions relevant for the etiology of affective disorders. Expand
Selective inhibitors of the FK506-binding protein 51 by induced fit.
TLDR
It is demonstrated that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice, providing the structural and functional basis for the development of mechanistically new antidepressants. Expand
Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin
TLDR
It is shown that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity, providing a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FK BP homologs. Expand
FKBP51 employs both scaffold and isomerase functions to promote NF-κB activation in melanoma
TLDR
FKBP51 promotes NF-κB activation by serving as an IKK scaffold as well as an isomerase, which has profound implications for designing novel melanoma therapies based on modulation of FKBP 51. Expand
Design, synthesis, and evaluation of gluten peptide analogs as selective inhibitors of human tissue transglutaminase.
TLDR
Proteolytically stable peptide inhibitors of human TG2 were designed containing acivicin or alternatively 6-diazo-5-oxo-norleucine (DON) as warheads, and the best of these inhibitors, Ac-PQP-(DON)-LPF-NH(2), was considerably more potent and selective than other TG2 inhibitors reported to date. Expand
A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease
TLDR
It is shown that corticotroph adenomas overexpress HSP90 compared to the normal pituitary, which suggests that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate H SP90 inhibitor. Expand
Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine
TLDR
Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. Expand
Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90.
TLDR
These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors. Expand
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