Crystal structures of a new class of allosteric effectors complexed to tryptophan synthase

Michael Weyand, Ilme Schlichting, Anna Marabotti, Andrea Mozzarelli

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Tryptophan synthase is a bifunctional α2β2 complex catalyzing the last two steps of L-tryptophan biosynthesis. The natural substrates of the α-subunit indole-3-glycerolphosphate and glyceraldehyde-3-phosphate, and the substrate analogs indole-3-propanolphosphate and DL-α-glycerol-3-phosphate are allosteric effectors of the β-subunit activity. It has been shown recently, that the indole-3-acetyl amino acids indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid are both α-subunit inhibitors and β-subunit allosteric effectors, whereas indole-3-acetyl-L-valine is only an α-subunit inhibitor (Marabotti, A., Cozzini, P., and Mozzarelli, A. (2000) Biochim. Biophys. Acta 1476, 287-299). The crystal structures of tryptophan synthase complexed with indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid show that both ligands bind to the active site such that the carboxylate moiety is positioned similarly as the phosphate group of the natural substrates. As a consequence, the residues of the α-active site that interact with the ligands are the same as observed in the indole 3-glycerolphosphate-enzyme complex. Ligand binding leads to closure of loop αL6 of the α-subunit, a key structural element of intersubunit communication. This is in keeping with the allosteric role played by these compounds. The structure of the enzyme complex with indole-3-acetyl-L-valine is quite different. Due to the hydrophobic lateral chain, this molecule adopts a new orientation in the α-active site. In this case, closure of loop αL6 is no longer observed, in agreement with its functioning only as an inhibitor of the α-subunit reaction.

Original languageEnglish
Pages (from-to)10647-10652
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number12
DOIs
Publication statusPublished - Mar 22 2002

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Tryptophan Synthase
Crystal structure
Glycerophosphates
Catalytic Domain
Valine
Ligands
Aspartic Acid
Substrates
Glyceraldehyde 3-Phosphate
indole
Biosynthesis
Enzymes
Tryptophan
Phosphates
Amino Acids
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Crystal structures of a new class of allosteric effectors complexed to tryptophan synthase. / Weyand, Michael; Schlichting, Ilme; Marabotti, Anna; Mozzarelli, Andrea.

In: Journal of Biological Chemistry, Vol. 277, No. 12, 22.03.2002, p. 10647-10652.

Research output: Contribution to journalArticle

Weyand, Michael ; Schlichting, Ilme ; Marabotti, Anna ; Mozzarelli, Andrea. / Crystal structures of a new class of allosteric effectors complexed to tryptophan synthase. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 12. pp. 10647-10652.
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AB - Tryptophan synthase is a bifunctional α2β2 complex catalyzing the last two steps of L-tryptophan biosynthesis. The natural substrates of the α-subunit indole-3-glycerolphosphate and glyceraldehyde-3-phosphate, and the substrate analogs indole-3-propanolphosphate and DL-α-glycerol-3-phosphate are allosteric effectors of the β-subunit activity. It has been shown recently, that the indole-3-acetyl amino acids indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid are both α-subunit inhibitors and β-subunit allosteric effectors, whereas indole-3-acetyl-L-valine is only an α-subunit inhibitor (Marabotti, A., Cozzini, P., and Mozzarelli, A. (2000) Biochim. Biophys. Acta 1476, 287-299). The crystal structures of tryptophan synthase complexed with indole-3-acetylglycine and indole-3-acetyl-L-aspartic acid show that both ligands bind to the active site such that the carboxylate moiety is positioned similarly as the phosphate group of the natural substrates. As a consequence, the residues of the α-active site that interact with the ligands are the same as observed in the indole 3-glycerolphosphate-enzyme complex. Ligand binding leads to closure of loop αL6 of the α-subunit, a key structural element of intersubunit communication. This is in keeping with the allosteric role played by these compounds. The structure of the enzyme complex with indole-3-acetyl-L-valine is quite different. Due to the hydrophobic lateral chain, this molecule adopts a new orientation in the α-active site. In this case, closure of loop αL6 is no longer observed, in agreement with its functioning only as an inhibitor of the α-subunit reaction.

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