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 Benkovic, Ian A. Wilson

Research output: Contribution to journalArticle

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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

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Phosphoribosylglycinamide Formyltransferase
Escherichia coli
Drug Therapy
Enzymes
Enzyme Inhibitors
Folic Acid
Catalytic Domain
Phosphates
Catalysis
Aspartic Acid
Antineoplastic Agents
Yeasts
Binding Sites
Electrons
Ions
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Biology

Cite this

Chen, Ping ; Schulze-Gahmen, Ursula ; Stura, Enrico A. ; Inglese, James ; Johnson, Dana L. ; Marolewski, Ariane ; Benkovic, Stephen ; Wilson, Ian A. / Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3·0 Å resolution. A target enzyme for chemotherapy. In: Journal of Molecular Biology. 1992 ; Vol. 227, No. 1. pp. 283-292.
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abstract = "The atomic structure of glycinamide ribonucleotide transformylase, an essential enzyme in purine biosynthesis, has been determined at 3·0 {\AA} 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.",
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Chen, P, Schulze-Gahmen, U, Stura, EA, Inglese, J, Johnson, DL, Marolewski, A, Benkovic, S & Wilson, IA 1992, 'Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3·0 Å resolution. A target enzyme for chemotherapy', Journal of Molecular Biology, vol. 227, no. 1, pp. 283-292. https://doi.org/10.1016/0022-2836(92)90698-J

Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3·0 Å resolution. A target enzyme for chemotherapy. / Chen, Ping; Schulze-Gahmen, Ursula; Stura, Enrico A.; Inglese, James; Johnson, Dana L.; Marolewski, Ariane; Benkovic, Stephen; Wilson, Ian A.

In: Journal of Molecular Biology, Vol. 227, No. 1, 05.09.1992, p. 283-292.

Research output: Contribution to journalArticle

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AU - Chen, Ping

AU - Schulze-Gahmen, Ursula

AU - Stura, Enrico A.

AU - Inglese, James

AU - Johnson, Dana L.

AU - Marolewski, Ariane

AU - Benkovic, Stephen

AU - Wilson, Ian A.

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N2 - 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.

AB - 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.

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