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Chem Biol. 2014 Oct 23;21(10):1278-1292. doi: 10.1016/j.chembiol.2014.08.016. Epub 2014 Oct 9.

Identification of Orai1 channel inhibitors by using minimal functional domains to screen small molecule microarrays.

Author information

1
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
2
Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 689-798 Ulsan, South Korea.
3
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
6
Department of Chemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: ricardo.dolmetsch@novartis.com.
8
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), 689-798 Ulsan, South Korea. Electronic address: cypark@unist.ac.kr.

Abstract

Store-operated calcium (SOC) channels are vital for activation of the immune cells, and mutations in the channel result in severe combined immunodeficiency in human patients. In lymphocytes, SOC entry is mediated by the Orai1 channel, which is activated by direct binding of STIM1. Here we describe an alternative approach for identifying inhibitors of SOC entry using minimal functional domains of STIM1 and Orai1 to screen a small-molecule microarray. This screen identified AnCoA4, which inhibits SOC entry at submicromolar concentrations and blocks T cell activation in vitro and in vivo. Biophysical studies revealed that AnCoA4 binds to the C terminus of Orai1, directly inhibiting calcium influx through the channel and also reducing binding of STIM1. AnCoA4, unlike other reported SOC inhibitors, is a molecule with a known binding site and mechanism of action. These studies also provide proof of principle for an approach to ion channel drug discovery.

PMID:
25308275
DOI:
10.1016/j.chembiol.2014.08.016
[Indexed for MEDLINE]
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