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Journal Article

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

MPS-Authors

Weyand,  Michael
Max Planck Institute of Molecular Physiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons98726

Schlichting,  Ilme
Abt. III: Physikalische Biochemie, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Citation

Weyand, M., Schlichting, I., Marabotti, A., & Mozzarelli, A. (2002). Crystal structures of a new class of allosteric effectors complexed to tryptophan synthase. Journal of Biological Chemistry, 277(12): 1, pp. 10647-10652. Retrieved from http://www.jbc.org/cgi/reprint/277/12/10647.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-0EB8-E
Abstract
Tryptophan synthase is a bifunctional alpha(2)/beta(2) complex catalyzing the last two steps of L-tryptophan biosynthesis. The natural substrates of the alpha-subunit indole-3- glycerolphosphate and glyceraldehyde-3-phosphate, and the substrate analogs indole-3-propanolphosphate and DL-alpha- glycerol-3-phosphate are allosteric effectors of the beta- 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 alpha-subunit inhibitors and beta-subunit allosteric effectors, whereas indole-3-acetyl-L- valine is only an alpha-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 alpha-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 alphaL6 of the alpha-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 alpha-active site. In this case, closure of loop alphaL6 is no longer observed, in agreement with its functioning only as an inhibitor of the a- subunit reaction.