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Dive into the research topics where Kathy Strauch is active.

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Featured researches published by Kathy Strauch.


Structure | 2001

Structure of CD40 ligand in complex with the Fab fragment of a neutralizing humanized antibody.

Michael Karpusas; Jodie Lucci; Janine Ferrant; Christopher D. Benjamin; Frederick R. Taylor; Kathy Strauch; Ellen Garber; Yen-Ming Hsu

BACKGROUND CD40 ligand (CD40L or CD154), a member of the tumor necrosis factor (TNF) family, plays a critical role in both humoral and cellular immune responses and has been implicated in biological pathways involving epithelial cells, fibroblasts, and platelets. Such a pathway is T cell-mediated B cell activation, a process that occurs through the interaction of CD40L with CD40 receptor expressed on B cells. It results in various B cell responses, including immunoglobulin isotype switching and B cell differentiation and proliferation. These responses can be inhibited by the monoclonal antibody 5c8, which binds with high affinity to CD40L. RESULTS To understand the structural basis of the inhibition, we determined the crystal structure of the complex of the extracellular domain of CD40L and the Fab fragment of humanized 5c8 antibody. The structure shows that the complex has the shape of a three-bladed propeller with three Fab fragments bound symmetrically to a CD40L homotrimer. To further study the nature of the antibody-antigen interface, we assessed the ability of 23 site-directed mutants of CD40L to bind to 5c8 and CD40 and analyzed the results in the context of the crystal structure. Finally, we observed via confocal microscopy that 5c8 binding to CD40L on the cell surface results in the formation of patches of clustered complexes. CONCLUSIONS The structure reveals that 5c8 neutralizes CD40L function by sterically blocking CD40 binding. The antigenic epitope is localized in a region of the surface that is likely to be structurally perturbed as a result of genetic mutations that cause hyper-IgM syndrome. The symmetric trimeric arrangement of the Fab fragments in the complex results in a geometry that facilitates the formation of large clusters of complexes on the cell surface.


ACS Chemical Biology | 2011

Small Molecule Inhibition of the TNF Family Cytokine CD40 Ligand Through a Subunit Fracture Mechanism

Laura Silvian; Jessica E. Friedman; Kathy Strauch; Teresa G. Cachero; Eric S. Day; Fang Qian; Brian T. Cunningham; Amy D. Fung; Lihong Sun; Gerald W. Shipps; Lihe Su; Zhongli Zheng; Gnanasambandam Kumaravel; Adrian Whitty

BIO8898 is one of several synthetic organic molecules that have recently been reported to inhibit receptor binding and function of the constitutively trimeric tumor necrosis factor (TNF) family cytokine CD40 ligand (CD40L, aka CD154). Small molecule inhibitors of protein-protein interfaces are relatively rare, and their discovery is often very challenging. Therefore, to understand how BIO8898 achieves this feat, we characterized its mechanism of action using biochemical assays and X-ray crystallography. BIO8898 inhibited soluble CD40L binding to CD40-Ig with a potency of IC(50) = 25 μM and inhibited CD40L-dependent apoptosis in a cellular assay. A co-crystal structure of BIO8898 with CD40L revealed that one inhibitor molecule binds per protein trimer. Surprisingly, the compound binds not at the surface of the protein but by intercalating deeply between two subunits of the homotrimeric cytokine, disrupting a constitutive protein-protein interface and breaking the proteins 3-fold symmetry. The compound forms several hydrogen bonds with the protein, within an otherwise hydrophobic binding pocket. In addition to the translational splitting of the trimer, binding of BIO8898 was accompanied by additional local and longer-range conformational perturbations of the protein, both in the core and in a surface loop. Binding of BIO8898 is reversible, and the resulting complex is stable and does not lead to detectable dissociation of the protein trimer. Our results suggest that a set of core aromatic residues that are conserved across a subset of TNF family cytokines might represent a generic hot-spot for the induced-fit binding of trimer-disrupting small molecules.


FEBS Journal | 2013

Structure of the extracellular domains of human and Xenopus Fn14: implications in the evolution of TWEAK and Fn14 interactions

Maria Pellegrini; Laure Willen; Dennis Krushinskie; Kathy Strauch; Hernan Cuervo; Eric S. Day; Pascal Schneider; Timothy S. Zheng

TWEAK (TNF homologue with weak apoptosis‐inducing activity) and Fn14 (fibroblast growth factor‐inducible protein 14) are members of the tumor necrosis factor (TNF) ligand and receptor super‐families. Having observed that Xenopus Fn14 cross‐reacts with human TWEAK, despite its relatively low sequence homology to human Fn14, we examined the conservation in tertiary fold and binding interfaces between the two species. Our results, combining NMR solution structure determination, binding assays, extensive site‐directed mutagenesis and molecular modeling, reveal that, in addition to the known and previously characterized β−hairpin motif, the helix‐loop‐helix motif makes an essential contribution to the receptor/ligand binding interface. We further discuss the insight provided by the structural analyses regarding how the cysteine‐rich domains of the TNF receptor super‐family may have evolved over time.


Science | 2001

BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF

Jeffrey Thompson; Sarah A. Bixler; Fang Qian; Kalpit A. Vora; Martin L. Scott; Teresa G. Cachero; Catherine Hession; Pascal Schneider; Irene Sizing; Colleen Mullen; Kathy Strauch; Mohammad Zafari; Christopher D. Benjamin; Jürg Tschopp; Jeffrey L. Browning; Christine Ambrose


Journal of Experimental Medicine | 2000

A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth.

Paul D. Rennert; Pascal Schneider; Teresa G. Cachero; Jeffrey Thompson; Luciana Trabach; Sylvie Hertig; Nils Holler; Fang Qian; Colleen Mullen; Kathy Strauch; Jeffrey L. Browning; Christine Ambrose; Jürg Tschopp


Journal of Molecular Biology | 2002

Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes

Michael Karpusas; Teresa G. Cachero; Fang Qian; Ann Boriack-Sjodin; Colleen Mullen; Kathy Strauch; Yen-Ming Hsu; Susan L. Kalled


Journal of Clinical Investigation | 2003

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

Nigel A. Calcutt; Karen L. Allendoerfer; Andrew P. Mizisin; Alicia Middlemas; Monica L. Burgers; Rigel Ranciato; Jean Dominique Delcroix; Frederick R. Taylor; Renee Shapiro; Kathy Strauch; Henryk Dudek; Thomas Engber; Alphonse Galdes; Lee L. Rubin; David R. Tomlinson


Biochemistry | 2006

Formation of virus-like clusters is an intrinsic property of the tumor necrosis factor family member BAFF (B cell activating factor).

Teresa G. Cachero; Ian M. Schwartz; Fang Qian; Eric S. Day; Claudia Bossen; Karine Ingold; Aubry Tardivel; Dennis Krushinskie; John K. Eldredge; Laura Silvian; Alexey A. Lugovskoy; Graham K. Farrington; Kathy Strauch; Pascal Schneider; Adrian Whitty


Biochemistry | 2006

Stoichiometry of LTβR binding to LIGHT

John K. Eldredge; Steven A. Berkowitz; Alan F. Corin; Eric S. Day; David Hayes; Werner Meier; Kathy Strauch; Mohammad Zafari; Madhavi Tadi; Graham K. Farrington


ACS Chemical Biology | 2011

Correction to Small Molecule Inhibition of the TNF Family Cytokine CD40 Ligand through a Subunit Fracture Mechanism

Laura Silvian; Jessica E. Friedman; Kathy Strauch; Teresa G. Cachero; Eric S. Day; Fang Qian; Brian T. Cunningham; Amy D. Fung; Lihong Sun; Gerald W. Shipps; Lihe Su; Zhongli Zheng; Gnanasambandam Kumaravel; Adrian Whitty

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