Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3·0 Å resolution. A target enzyme for chemotherapy

Ping Chen, Ursula Schulze-Gahmen, Enrico A. Stura, James Inglese, Dana L. Johnson, Ariane Marolewski, Stephen J. Benkovic, Ian A. Wilson

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Abstract

The atomic structure of glycinamide ribonucleotide transformylase, an essential enzyme in purine biosynthesis, has been determined at 3·0 Å resolution. The last three C-terminal residues and a sequence stretch of 18 residues (residues 113 to 130) are not visible in the electron density map. The enzyme forms a dimer in the crystal structure. Each monomer is divided into two domains, which are connected by a central mainly parallel seven-stranded β-sheet. The N-terminal domain contains a Rossmann type mononucleotide fold with a phosphate ion bound to the C-terminal end of the first β-strand. A long narrow cleft stretches from the phosphate to a conserved aspartic acid, Aspl44, which has been suggested as an active-site residue. The cleft is lined by a cluster of residues, which are conserved between bacterial, yeast, avian and human enzymes, and likely represents the binding pocket and active site of the enzyme. GAR Tfase binds a reduced folate cofactor and glycinamide ribonucleotide for the catalysis of one of the initial steps in purine biosynthesis. Folate analogs and multi-substrate inhibitors of the enzyme have antineoplastic effects and the structure determination of the unliganded enzyme and enzyme-inhibitor complexes will aid the development of anti-cancer drugs.

Original languageEnglish (US)
Pages (from-to)283-292
Number of pages10
JournalJournal of Molecular Biology
Volume227
Issue number1
DOIs
StatePublished - Sep 5 1992

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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    Chen, P., Schulze-Gahmen, U., Stura, E. A., Inglese, J., Johnson, D. L., Marolewski, A., Benkovic, S. J., & Wilson, I. A. (1992). Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3·0 Å resolution. A target enzyme for chemotherapy. Journal of Molecular Biology, 227(1), 283-292. https://doi.org/10.1016/0022-2836(92)90698-J