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Titolo:
Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase
Autore:
Pellegrini, M; Liehr, S; Fisher, AL; Laub, PB; Cooperman, BS; Mierke, DF;
Indirizzi:
Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Providence, RI 02912 USA Brown Univ Providence RI USA 02912 v Biol & Med, Providence, RI 02912 USA Brown Univ, Dept Chem, Providence, RI 02912 USA Brown Univ Providence RI USA 02912 v, Dept Chem, Providence, RI 02912 USA Univ Penn, Dept Chem, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Dept Chem, Philadelphia, PA 19104 USA Fox Chase Canc Ctr, Philadelphia, PA 19111 USA Fox Chase Canc Ctr Philadelphia PA USA 19111 , Philadelphia, PA 19111 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 40, volume: 39, anno: 2000,
pagine: 12210 - 12215
SICI:
0006-2960(20001010)39:40<12210:SOOPIO>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
RELAXATION MATRIX APPROACH; NUCLEAR-MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; R1 SUBUNIT; ENSEMBLE; TERMINUS; EXCHANGE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Cooperman, BS Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Providence, RI 02912 USA Brown Univ Providence RI USA 02912 Providence, RI 02912 USA
Citazione:
M. Pellegrini et al., "Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase", BIOCHEM, 39(40), 2000, pp. 12210-12215

Abstract

Mammalian ribonucleotide reductase (mRR), a potential target for cancer intervention, is composed of two subunits, mR1 and mR2, whose association is critical for enzyme activity. Tn this article we describe the structural features of the mRR-inhibitor Ac-F-[ELAK]-DF (Peptide 3) while bound to the mR1 subunit as determined by transferred NOEs. Peptide 3 is a cyclic analogue of the N-acetylated form of the heptapeptide C-terminus of the mR2 subunit (Ac-FTLDADF), which is the link between the two subunits and previously shown to be the minimal sequence inhibitor mRR by competing with mR2 for binding to mR1. Structural refinement employing an ensemble-based, full-relaxation matrix approach resulted in two structures varying in the conformations of F-1 and the cyclic lactam side chains of E-2 and K-5. The remainder ofthe molecule, both backbone and side chains, is extremely well-defined, with an RMSD of 0.54 Angstrom. The structural features of this conformationally constrained analogue provide unique insight into the requirements for binding to mR1, critical for further inhibitor development.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 18:28:16