1FOZ

STRUCTURE OF CYCLIC PEPTIDE INHIBITORS OF MAMMALIAN RIBONUCLEOTIDE REDUCTASE

Summary for 1FOZ

• Entry DOI: 10.2210/pdb1foz/pdb
• Descriptor: SYNTHETIC CYCLIC PEPTIDE (1 entity in total)
• Functional Keywords: transferred noes, irma refinement, ribonucleotide reductase inhibitors, oxidoreductase inhibitor
• Total number of polymer chains: 1
• Total formula weight: 940.03

Authors

Pellegrini, M.,Liehr, S.,Fisher, A.L.,Cooperman, B.S.,Mierke, D.F. (deposition date: 2000-08-29, release date: 2000-11-22, Last modification date: 2011-07-13)

Primary citation

Pellegrini, M.,Liehr, S.,Fisher, A.L.,Laub, P.B.,Cooperman, B.S.,Mierke, D.F.
Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase.
Biochemistry, 39:12210-12215, 2000

PubMed 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. In this article we describe the structural features of the mRR-inhibitor Ac-F-c[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 A. The structural features of this conformationally constrained analogue provide unique insight into the requirements for binding to mR1, critical for further inhibitor development.

PubMed: 11015199
DOI: 10.1021/bi001323a

Experimental method

SOLUTION NMR