RGD Reference Report - A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists.

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A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists.
Authors:	Eckart, K Jahn, O Radulovic, J Tezval, H Van Werven, L Spiess, J
Citation:	Eckart K, etal., Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11142-7.
RGD ID:	5508795
Pubmed:	PMID:11572971 (View Abstract at PubMed)
PMCID:	PMC58697 (View Article at PubMed Central)
DOI:	DOI:10.1073/pnas.211424998 (Journal Full-text)
In view of the observation that corticotropin-releasing factor (CRF) affects several brain functions through at least two subtypes of G protein-dependent receptors and a binding protein (CRFBP), we have developed synthetic strategies to provide enhanced binding specificity. Human/rat CRF (h/rCRF) and the CRF-like peptide sauvagine (Svg), differing in their affinities to CRFBP by two orders of magnitude, were used to identify the residues determining binding to CRFBP. By amino acid exchanges, it was found that Ala(22) of h/rCRF was responsible for this peptide's high affinity to CRFBP, whereas Glu(21) located in the equivalent position of Svg prevented high affinity binding to CRFBP. Accordingly, [Glu(22)]h/rCRF was not bound with high affinity to CRFBP in contrast to [Ala(21)]Svg, which exhibited such high affinity. Furthermore, the affinity of both peptides to either CRF receptor (CRFR) subtype was not reduced by these replacements, and their subtype preference was not changed. Thus, exchange of Ala and Glu and vice versa in positions 22 and 21 of h/rCRF and Svg, respectively, serves as a switch discriminating between CRFBP and CRFR. On the basis of this switch function, development of new specific CRF agonists and antagonists is expected to be facilitated. One application was the modification of the CRF antagonist astressin (Ast), whose employment in animal experiments is limited by its low solubility in cerebrospinal fluid. Introduction of Glu residues into Ast generated with [Glu(11,16)]Ast an acidic astressin, which efficiently antagonized in vivo the CRFR1-dependent reduction of locomotion induced by ovine CRF without detectable binding to CRFBP.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Crhbp	Rat	corticotropin-releasing hormone binding		IPI	Crh (Rattus norvegicus)		RGD
Crh	Rat	corticotropin-releasing hormone receptor 2 binding		IPI	Crhr2 (Mus musculus)		RGD
Crhbp	Rat	peptide binding		IDA		astressin and sauvagine	RGD
Crh	Rat	protein binding		IPI	Crhbp (Rattus norvegicus)		RGD

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Genes (Rattus norvegicus)

Crh (corticotropin releasing hormone)

Crhbp (corticotropin releasing hormone binding protein)

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A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists.