High-Resolution Structure and Inhibition of the Schizophrenia-Linked Pseudokinase ULK4
Abstract not provided
Khamrui, Susmita↗
Engineering topics
Schlessinger, Avner
Publications and source records attributed to Schlessinger, Avner.
Predicting kinase inhibitors using bioactivity matrix derived informer sets
Prediction of compounds that are active against a desired biological target is a common step in drug discovery efforts. Virtual screening methods seek some active-enriched fraction of a library for experimental testing. Where data are too scarce to train supervised learning models for compound prioritization, initial screening must provide the necessary data. Commonly, such an initial library is selected on the basis of chemical diversity by some pseudo-random process (for example, the first few plates of a larger library) or by selecting an entire smaller library. These approaches may not produce a sufficient number or diversity of actives. An alternative approach is to select an informer set of screening compounds on the basis of chemogenomic information from previous testing of compounds against a large number of targets. We compare different ways of using chemogenomic data to choose a small informer set of compounds based on previously measured bioactivity data. We develop this Informer-Based-Ranking (IBR) approach using the Published Kinase Inhibitor Sets (PKIS) as the chemogenomic data to select the informer sets. We test the informer compounds on a target that is not part of the chemogenomic data, then predict the activity of the remaining compounds based on the experimental informer data and the chemogenomic data. Through new chemical screening experiments, we demonstrate the utility of IBR strategies in a prospective test on three kinase targets not included in the PKIS.
59 BASIC BIOLOGICAL SCIENCES↗
Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity
The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either α-Klotho or β-Klotho receptors. Structural analyses of ligandoccupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to β-Klotho or α-Klotho, respectively. They have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling. In this paper we describe the crystal structure the C-terminal tail of FGF19 (FGF19 CT ) bound to sKLB and demonstrate that FGF19 CT and FGF21 CT bind to the same binding site on sKLB, via a multiturn D-P motif to site 1 and via a SP- S motif to the pseudoglycoside hydrolase region (site 2). Binding affinities to sKLB and cellular stimulatory activities of FGF19 CT , FGF21 CT , and a variety of chimeric mutants to cells expressing β-Klotho together with FGFR1c or FGFR4 were also analyzed. These experiments as well as detailed comparison of the structures of free and ligand-occupied sKLB to the structure of ligandoccupied sKLA reveal a general mechanism for recognition of endocrine FGFs by Klotho proteins and regulatory interactions with FGFRs that control their pleiotropic cellular responses.
59 BASIC BIOLOGICAL SCIENCES↗