Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase

被引:20
|
作者
Pellegrini, M
Liehr, S
Fisher, AL
Laub, PB
Cooperman, BS [1 ]
Mierke, DF
机构
[1] Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Providence, RI 02912 USA
[2] Brown Univ, Dept Chem, Providence, RI 02912 USA
[3] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA
[4] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA
关键词
D O I
10.1021/bi001323a
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 of the 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.
引用
收藏
页码:12210 / 12215
页数:6
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