Journal article
Fragment‐Based Nuclear Magnetic Resonance Screen against a Regulator of G Protein Signaling Identifies a Binding “Hot Spot”
Chembiochem : a European journal of chemical biology, Vol.22(9), pp.1609-1620
02/16/2021
DOI: 10.1002/cbic.202000740
PMID: 33480159
Abstract
Regulator of G protein signaling (RGS) proteins have attracted attention as a result of their primary role in directing the specificity as well as the temporal and spatial aspects of G protein-coupled receptor signaling. In addition, alterations in RGS protein expression have been observed in a number of disease states, including certain cancers. In this area, RGS17 is of particular interest. It has been demonstrated that, while RGS17 is expressed primarily in the central nervous system, it has been found to be inappropriately expressed in lung, prostate, breast, cervical, and hepatocellular carcinomas. Overexpression of RGS17 leads to dysfunction in inhibitory G protein signaling and an overproduction of the intracellular second messenger cAMP, which in turn alters the transcription patterns of proteins known to promote various cancer types. Suppressing RGS17 expression with RNA interference (RNAi) has been found to decrease tumorigenesis and sufficiently prevents cancer cell migration, leading to the hypothesis that pharmacological blocking of RGS17 function could be useful in anticancer therapies. We have identified small-molecule fragments capable of binding the RGS homology (RH) domain of RGS17 by using a nuclear magnetic resonance fragment-based screening approach. By chemical shift mapping of the two-dimensional 15 N,1 H heteronuclear single quantum coherence (HSQC) spectra of the backbone-assigned 15 N-labeled RGS17-RH, we determined the fragment binding sites to be distant from the Gα interface. Thus, our study identifies a putative fragment binding site on RGS17 that was previously unknown.
Keywords: NMR spectroscopy; binding sites; fragment-based lead discovery; protein-protein interactions; regulator of G protein signaling.
© 2021 Wiley-VCH GmbH.
Details
- Title: Subtitle
- Fragment‐Based Nuclear Magnetic Resonance Screen against a Regulator of G Protein Signaling Identifies a Binding “Hot Spot”
- Creators
- Michael P Hayes - Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of Iowa 180 S Grand Avenue, CPB 538 Iowa City IA 52245 USA, Present address: Beckman Coulter Indianapolis IN 46268 USAJoseph B O'Brien - Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of Iowa 180 S Grand Avenue, CPB 538 Iowa City IA 52245 USARachel A Crawford - Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of Iowa 180 S Grand Avenue, CPB 538 Iowa City IA 52245 USAC. Andrew Fowler - NMR Facility, Roy J. and Lucille A. Carver College of Medicine University of Iowa 285 Newton Rd Iowa City IA 52245 USA, Present address: Bruker Biospin Corporation Billerica MA 01821–3991 USALiping Yu - NMR Facility, Roy J. and Lucille A. Carver College of Medicine University of Iowa 285 Newton Rd Iowa City IA 52245 USAJonathan A Doorn - Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of Iowa 180 S Grand Avenue, CPB 538 Iowa City IA 52245 USA, Iowa Neuroscience Institute Roy J. and Lucille A. Carver College of Medicine University of Iowa Iowa City IA 52242 USADavid L Roman - Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy University of Iowa 180 S Grand Avenue, CPB 538 Iowa City IA 52245 USA, Iowa Neuroscience Institute Roy J. and Lucille A. Carver College of Medicine University of Iowa Iowa City IA 52242 USA
- Resource Type
- Journal article
- Publication Details
- Chembiochem : a European journal of chemical biology, Vol.22(9), pp.1609-1620
- DOI
- 10.1002/cbic.202000740
- PMID
- 33480159
- NLM abbreviation
- Chembiochem
- ISSN
- 1439-4227
- eISSN
- 1439-7633
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: 5R01CA160470
- Language
- English
- Date published
- 02/16/2021
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Medicine Administration; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070998902771
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