PMID: 9653552Jul 8, 1998Paper

Inhibiting the dimeric restriction endonuclease EcoRI using interfacial helical peptides

Chemistry & Biology
M Brickner, J Chmielewski

Abstract

Many enzymes are active only in a dimeric form, including a variety of type II restriction endonucleases. Disruption of subunit interactions is therefore a potential method for multimeric enzyme inhibition. EcoRI is a homodimeric restriction endonuclease, the dimeric interface of which consists of a four-helix bundle. We set out to design helical peptides to interact with this interface and block dimer formation, thus rendering EcoRI inactive. Here we describe two synthetic, helical peptides based on the interfacial region of EcoRI. Both peptides inhibit the enzyme, but the peptide derived from the alpha 4 helix of EcoRI had both a higher helical content and better efficacy than a variant peptide, alpha 4(Leu), that has three Ile-->Leu mutations (IC50 values of 27 microM and 90 microM, and helical contents of 29% and 10%, respectively). Size-exclusion chromatography confirmed that the alpha 4 peptide disrupted dimerization of EcoRI, and circular dichroism indicated that EcoRI remained folded upon binding to alpha 4. Inhibition with alpha 4 and alpha 4(Leu) was shown to be specific for EcoRI, as the dimeric restriction enzyme PvuII was not affected by the peptides. Interfacial peptide inhibitors of the dimeric EcoRI were obtaine...Continue Reading

References

Oct 1, 1992·Protein Science : a Publication of the Protein Society·L M BabéC S Craik
Jan 1, 1991·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·G CosentinoN Dansereau
Feb 1, 1995·Current Opinion in Structural Biology·A K Aggarwal
Jul 30, 1993·Biochemical and Biophysical Research Communications·H J SchrammW Schramm

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Citations

Mar 31, 2004·The Journal of Peptide Research : Official Journal of the American Peptide Society·A K GalandeA F Spatola
Dec 26, 2002·Journal of Molecular Recognition : JMR·A V VeselovskyP Janssen
Dec 26, 2001·Chemical Reviews·M W Peczuh, A D Hamilton

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