1d6s Citations

Ligand binding induces a large conformational change in O-acetylserine sulfhydrylase from Salmonella typhimurium.

J Mol Biol 291 941-53 (1999)
Cited: 70 times
EuropePMC logo PMID: 10452898

Abstract

Covalent binding of L-methionine as an external aldimine to the pyridoxal 5'-phosphate-cofactor in the K41A mutant of O-acetylserine sulfhydrylase from Salmonella typhimurium induces a large conformational change in the protein. Methionine mimics the action of the substrate O-acetyl-L-serine during catalysis. The alpha-carboxylate moiety of L-methionine in external aldimine linkage with the active site pyridoxal 5'-phosphate forms a hydrogen bonding network to the "asparagine-loop" P67-T68-N69-G70 which adopts a different conformation than in the native protein. The side-chain nitrogen of Asn69 moves more than 7 A to make a hydrogen bond to the alpha-carboxylate group of the inhibitor. As the external aldimine is formed, the PLP tilts by 13 degrees along its longitudinal axis such that C4' moves toward the entrance to the active site and the side-chain of the methionine is directed toward the active site entrance. The local rearrangement acts as a trigger to induce a large global conformational change in the protein. A subdomain comprised of beta-strand 4, alpha-helix 3, beta-strand 5 and alpha-helix 4 moves towards the active site by a rotation of 7 degrees. This subdomain movement results in a reduction of the severe twist of its central beta-sheet and reduces the active site entrance to a small hole, giving access only to small molecules like sulfide, the second substrate, or acetate, the first product.

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Reviews citing this publication (7)

  1. Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein. Banerjee R, Zou CG. Arch Biochem Biophys 433 144-156 (2005)
  2. Functional analysis of the cysteine synthase protein complex from plants: structural, biochemical and regulatory properties. Wirtz M, Hell R. J Plant Physiol 163 273-286 (2006)
  3. Synthesis of the sulfur amino acids: cysteine and methionine. Wirtz M, Droux M. Photosynth Res 86 345-362 (2005)
  4. The enzymology of cystathionine biosynthesis: strategies for the control of substrate and reaction specificity. Aitken SM, Kirsch JF. Arch Biochem Biophys 433 166-175 (2005)
  5. The cysteine regulatory complex from plants and microbes: what was old is new again. Jez JM, Dey S. Curr Opin Struct Biol 23 302-310 (2013)
  6. Moonlighting O-acetylserine sulfhydrylase: New functions for an old protein. Campanini B, Benoni R, Bettati S, Beck CM, Hayes CS, Mozzarelli A. Biochim Biophys Acta 1854 1184-1193 (2015)
  7. Combatting antimicrobial resistance via the cysteine biosynthesis pathway in bacterial pathogens. Hicks JL, Oldham KEA, McGarvie J, Walker EJ. Biosci Rep 42 BSR20220368 (2022)

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