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			PubMed Journals: J Biol Chem

  Source:		PMID: 12235136


    		J Biol Chem. 2002 Nov 29;277(48):45793-802.
     		Epub 2002 Sep 13.

			Bi-functional, substrate mimicking RNA inhibits
			MSK1-mediated cAMP-response element-binding
			protein phosphorylation and reveals magnesium
			ion-dependent conformational changes of
			the kinase.

			Hamm J(1), Alessi DR, Biondi RM.

			Author Information
			(1) Department of Biochemistry,
			University of Dundee, Dundee, United Kingdom.
			jorg.hamm@unito.it

			The design of specific inhibitors for protein
			kinases is an important step toward elucidation
			of intracellular signal transduction pathways
			and to guide drug discovery programs. We
			devised a model approach to generate specific,
			competitive kinase inhibitors by isolating
			substrate mimics containing two independent
			binding sites with an anti-idiotype strategy
			from combinatorial RNA libraries. As a general
			test for the ability to generate highly
			specific kinase inhibitors, we selected
			the transcription factor cAMP-response
			element-binding protein (CREB) that is
			phosphorylated on the same serine residue
			by the protein kinase MSK1 as well as by
			RSK1. The sequences and structures of these
			kinases are very similar, about 60% of their
			amino acids are identical. Nevertheless,
			we can demonstrate that the selected RNA
			inhibitors inhibit specifically CREB phosphorylation
			by MSK1 but do not affect CREB phosphorylation
			by RSK1. The inhibitors interact preferentially
			with the inactive form of MSK1. Furthermore,
			we demonstrate that RNA ligands can be
			conformation-specific probes, and this feature
			allowed us to describe magnesium ion-dependent
			conformational changes of MSK1 upon activation.

			DOI: 10.1074/jbc.M205072200 PMID: 12235136
			[Indexed for MEDLINE]

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