Talk abstracts
Talk on Saturday 11:45-12:00pm submitted by Brittany Morgan
Selective Small Molecule Targeting of Homologous RNA-Binding Proteins
Johann M. Roque (Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN), Julia A. Haas (Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN), Beth P. Anderson (Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN), Ariel J. Thelander (Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN), Blanton S. Tolbert (Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA), Brittany S. Morgan (Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN)
Abstract:
RNA-Binding Proteins (RBPs) are exceptional therapeutics targets in a multitude of cancers and neurological diseases; yet despite their therapeutic promise, few chemical probes and/or drugs have been developed for RBPs. One of the major challenges is the abundance and exceptionally high structural conservation of RNA-binding domains (RBDs), where the sites of greatest diversity are in “unligandable” dynamic loops and linkers. Herein, we describe the selective targeting of conserved cysteine residues located in the dynamic loops of two homologous RBPs: heterogenous nuclear RiboNucleoProteins (hnRNPs) H and F. Specifically, the ligands target quasi-RNA Recognition Motifs 1 and 2 (qRRMs1,2), which share a highly conserved tertiary structure, greater than 85% sequence similarity, yet have unique molecular motions and conformational ensembles. We hypothesized that the slower protein motions in hnRNP H qRRMs1,2 would lead to longer-lived, pocket-like structures that could be exploited for selective ligand targeting. Indeed, covalent fragments were identified for qRRMs1,2 and optimized to have ten-fold selectivity for hnRNP H. Furthermore, traditional structure-affinity relationships were elucidated for the lead ligand, which targets a cysteine residue in a dynamic loop substructure. Our current efforts are focused on improving the potency and selectivity of the lead ligand through fragment building strategies and utilizing biomolecular NMR and molecular dynamics to explore the basis of ligand recognition and selectivity. The guiding principles discovered will be first-in-kind, describing how molecular motions in dynamic loops can be harnessed for ligand selectivity. The principles will be key for developing the first small molecules for hnRNP H into proteome-wide, selective chemical probes and for identifying selective small molecules for an array of other RBPs. The selective targeting of RBDs and RBPs will revolutionize our understanding of RBP structure, function, and therapeutic potential, and it will also establish a precedent of exploiting protein loops and dynamics for selective ligand targeting in chemical biology and drug discovery
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