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Title: The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore

Abstract

Eukaryotic ribonucleotide reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is a target for cancer therapy. RR activity requires formation of a complex between subunits R1 and R2 in which the R2 C-terminal peptide binds to R1. Here we report crystal structures of heterocomplexes containing mammalian R2 C-terminal heptapeptide, P7 (Ac-{sup 1}FTLDADF{sup 7}) and its peptidomimetic P6 ({sup 1}Fmoc(Me)PhgLDChaDF{sup 7}) bound to Saccharomyces cerevisiae R1 (ScR1). P7 and P6, both of which inhibit ScRR, each bind at two contiguous sites containing residues that are highly conserved among eukaryotes. Such binding is quite distinct from that reported for prokaryotes. The Fmoc group in P6 peptide makes several hydrophobic interactions that contribute to its enhanced potency in binding to ScR1. Combining all of our results, we observe three distinct conformations for peptide binding to ScR1. These structures provide pharmacophores for designing highly potent nonpeptide class I RR inhibitors.

Authors:
; ; ; ; ; ; ;  [1];  [2];  [2]
  1. (Case Western)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006774
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 51; Journal Issue: (15) ; 08, 2008; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; NEOPLASMS; NUCLEOSIDES; OXIDOREDUCTASES; PEPTIDES; RESIDUES; SACCHAROMYCES CEREVISIAE; TARGETS; THERAPY

Citation Formats

Xu, Hai, Fairman, James W., Wijerathna, Sanath R., Kreischer, Nathan R., LaMacchia, John, Helmbrecht, Elizabeth, Cooperman, Barry S., Dealwis, Chris, Tennessee-K), and UPENN). The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore. United States: N. p., 2008. Web. doi:10.1021/jm800350u.
Xu, Hai, Fairman, James W., Wijerathna, Sanath R., Kreischer, Nathan R., LaMacchia, John, Helmbrecht, Elizabeth, Cooperman, Barry S., Dealwis, Chris, Tennessee-K), & UPENN). The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore. United States. doi:10.1021/jm800350u.
Xu, Hai, Fairman, James W., Wijerathna, Sanath R., Kreischer, Nathan R., LaMacchia, John, Helmbrecht, Elizabeth, Cooperman, Barry S., Dealwis, Chris, Tennessee-K), and UPENN). Tue . "The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore". United States. doi:10.1021/jm800350u.
@article{osti_1006774,
title = {The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore},
author = {Xu, Hai and Fairman, James W. and Wijerathna, Sanath R. and Kreischer, Nathan R. and LaMacchia, John and Helmbrecht, Elizabeth and Cooperman, Barry S. and Dealwis, Chris and Tennessee-K) and UPENN)},
abstractNote = {Eukaryotic ribonucleotide reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is a target for cancer therapy. RR activity requires formation of a complex between subunits R1 and R2 in which the R2 C-terminal peptide binds to R1. Here we report crystal structures of heterocomplexes containing mammalian R2 C-terminal heptapeptide, P7 (Ac-{sup 1}FTLDADF{sup 7}) and its peptidomimetic P6 ({sup 1}Fmoc(Me)PhgLDChaDF{sup 7}) bound to Saccharomyces cerevisiae R1 (ScR1). P7 and P6, both of which inhibit ScRR, each bind at two contiguous sites containing residues that are highly conserved among eukaryotes. Such binding is quite distinct from that reported for prokaryotes. The Fmoc group in P6 peptide makes several hydrophobic interactions that contribute to its enhanced potency in binding to ScR1. Combining all of our results, we observe three distinct conformations for peptide binding to ScR1. These structures provide pharmacophores for designing highly potent nonpeptide class I RR inhibitors.},
doi = {10.1021/jm800350u},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (15) ; 08, 2008,
volume = 51,
place = {United States},
year = {2008},
month = {8}
}