Novel peptide ligands of RGS4 from a focused one-bead, one-compound library

Rebecca A Roof; Katarzyna Sobczyk-Kojiro; Anjanette J Turbiak; David L Roman; Irina D Pogozheva; Levi L Blazer; Richard R Neubig; Henry I Mosberg

doi:10.1111/j.1747-0285.2008.00687.x

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Novel peptide ligands of RGS4 from a focused one-bead, one-compound library

Journal article

Open access

Novel peptide ligands of RGS4 from a focused one-bead, one-compound library

Rebecca A Roof, Katarzyna Sobczyk-Kojiro, Anjanette J Turbiak, David L Roman, Irina D Pogozheva, Levi L Blazer, Richard R Neubig and Henry I Mosberg

Chemical biology & drug design, Vol.72(2), pp.111-119

08/2008

DOI: 10.1111/j.1747-0285.2008.00687.x

PMCID: PMC2917810

PMID: 18637987

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Abstract

Regulators of G protein signaling accelerate GTP hydrolysis by G alpha subunits and profoundly inhibit signaling by G protein-coupled receptors. The distinct expression patterns and pathophysiologic regulation of regulators of G protein signaling proteins suggest that inhibitors may have therapeutic potential. We previously reported the design, mechanistic evaluation, and structure-activity relationships of a disulfide-containing cyclic peptide inhibitor of RGS4, YJ34 (Ac-Val-Lys-c[Cys-Thr-Gly-Ile-Cys]-Glu-NH(2), S-S) (Roof et al., Chem Biol Drug Des, 67, 2006, 266). Using a focused one-bead, one-compound peptide library that contains features known to be necessary for the activity of YJ34, we now identify peptides that bind to RGS4. Six peptides showed confirmed binding to RGS4 by flow cytometry. Two analogs of peptide 2 (Gly-Thr-c[Cys-Phe-Gly-Thr-Cys]-Trp-NH(2), S-S with a free or acetylated N-terminus) inhibited RGS4-stimulated G alpha(o) GTPase activity at 25-50 microM. They selectively inhibit RGS4 but not RGS7, RGS16, and RGS19. Their inhibition of RGS4 does not depend on cysteine-modification of RGS4, as they do not lose activity when all cysteines are removed from RGS4. Peptide 2 has been modeled to fit in the same binding pocket predicted for YJ34 but in the reverse orientation.

Protein Structure, Tertiary

Amino Acid Sequence

Peptides - metabolism

Peptides - chemistry

Databases, Protein

RGS Proteins - chemistry

Models, Molecular

Protein Binding

RGS Proteins - metabolism

Ligands

Details

Title: Subtitle: Novel peptide ligands of RGS4 from a focused one-bead, one-compound library
Creators: Rebecca A Roof - Department of Pharmacology, University of Michigan, 1301 MSRB III/SPC5632, Ann Arbor, MI 48103, USA
Katarzyna Sobczyk-Kojiro
Anjanette J Turbiak
David L Roman
Irina D Pogozheva
Levi L Blazer
Richard R Neubig
Henry I Mosberg
Resource Type: Journal article
Publication Details: Chemical biology & drug design, Vol.72(2), pp.111-119
Publisher: England
DOI: 10.1111/j.1747-0285.2008.00687.x
PMID: 18637987
PMCID: PMC2917810
ISSN: 1747-0277
eISSN: 1747-0285
Grant note: DA03910 / NIDA NIH HHS R01 DA003910 / NIDA NIH HHS R01 DA003910-25 / NIDA NIH HHS T32 GM008597 / NIGMS NIH HHS R01 GM039561-21 / NIGMS NIH HHS T32 GM00008597 / NIGMS NIH HHS GM39561 / NIGMS NIH HHS R01 GM039561 / NIGMS NIH HHS
Language: English
Date published: 08/2008
Academic Unit: Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984065498502771

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