title: Crystal structures of a new class of allosteric effectors complexed to tryptophan synthase.
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 alpha-subunit reaction.
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung für Physikalische Biochemie, D-44227 Dortmund, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weyand
authors.forename: Ilme
authors.initials: I
authors.lastname: Schlichting
authors.forename: Anna
authors.initials: A
authors.lastname: Marabotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D000495:Allosteric Site; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006860:Hydrogen Bonding; D007210:Indoleacetic Acids / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D013997:Time Factors; D014367:Tryptophan Synthase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D007210:Indoleacetic Acids; D007211:Indoles; D008024:Ligands; C116425:indole-3-acetylglycine; D001224:Aspartic Acid; C030737:indoleacetic acid; D014367:Tryptophan Synthase; D005998:Glycine