Showing papers by "Svend Kjaer published in 2019"
TL;DR: The BTNL3 IgV domain binds directly and specifically to a human Vγ4+ TCR, “LES” with an affinity comparable to many αβ TCR-peptide major histocompatibility complex interactions, which can employ two discrete binding modalities: a non-clonotypic, superantigen-like interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive �
84 citations
TL;DR: The development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause is described.
Abstract: NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 μM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 μM) and isoquinoline 45 (IC50 0.085 μM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.
22 citations
TL;DR: The exchange factor FARP2 is identified as a polarity-determining protein that is a ‘RIPR’ motif-dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation.
Abstract: The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Amongst the controls determining polarity are the PAR proteins, PAR6/aPKCι/PAR3, regulating both known and unknown effectors. Here we identify FARP2 as a "RIPR" motif dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain-Kinase domain interaction and detachment promoted by aPKCι dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42 consistent with upstream regulation of the polarising PAR6-aPKCι complex. However, it is shown that aPKCι acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCι−FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCι and other Cdc42 effectors
12 citations