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Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novel inhibitor.

Steegborn C, Laber B, Messerschmidt A, Huber R, Clausen T
J Mol Biol 311 789-801 (2001)
Related entries: 1i43, 1i48

Cited: 12 times
EuropePMC logo PMID: 11518531

Abstract

Cystathionine gamma-synthase catalyzes the committed step of methionine biosynthesis. This pathway is unique to microorganisms and plants, rendering the enzyme an attractive target for the development of antimicrobials and herbicides. We solved the crystal structures of complexes of cystathionine gamma-synthase (CGS) from Nicotiana tabacum with inhibitors of different compound classes. The complex with the substrate analog dl-E-2-amino-5-phosphono-3-pentenoic acid verifies the carboxylate-binding function of Arg423 and identifies the phosphate-binding pocket of the active site. The structure shows the function of Lys165 in specificity determination and suggests a role for the flexible side-chain of Tyr163 in catalysis. The importance of hydrophobic interactions for binding to the active-site center is highlighted by the complex with 3-(phosphonomethyl)pyridine-2-carboxylic acid. The low affinity of this compound is due to the non-optimal arrangement of the functional groups binding to the phosphate and carboxylate-recognition site, respectively. The newly identified inhibitor 5-carboxymethylthio-3-(3'-chlorophenyl)-1,2,4-oxadiazol, in contrast, shows the highest affinity to CGS reported so far. This affinity is due to binding to an additional active-site pocket not used by the physiological substrates. The inhibitor binds to the carboxylate-recognition site, and its tightly bent conformation enables it to occupy the novel binding pocket between Arg423 and Ser388. The described structures suggest improvements for known inhibitors and give guidelines for the development of new lead compounds.

Articles - 1i41 mentioned but not cited (2)

  1. Exploration of the active site of Escherichia coli cystathionine γ-synthase. Jaworski AF, Lodha PH, Manders AL, Aitken SM. Protein Sci 21 1662-1671 (2012)
  2. Expression, purification and preliminary crystallographic analysis of O-acetylhomoserine sulfhydrylase from Mycobacterium tuberculosis. Yin J, Garen CR, Bateman K, Yu M, Lyon EZ, Habel J, Kim H, Hung LW, Kim CY, James MN. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 959-963 (2011)


Reviews citing this publication (3)

  1. Implications of protein flexibility for drug discovery. Teague SJ. Nat Rev Drug Discov 2 527-541 (2003)
  2. Structural biology of plant sulfur metabolism: from assimilation to biosynthesis. Ravilious GE, Jez JM. Nat Prod Rep 29 1138-1152 (2012)
  3. Comparative genome analysis of the first Listeria monocytogenes core genome multi-locus sequence types CT2050 AND CT2051 strains with their close relatives. Nwaiwu O. AIMS Microbiol 8 61-72 (2022)

Articles citing this publication (7)

  1. α-Vinylic Amino Acids: Occurrence, Asymmetric Synthesis and Biochemical Mechanisms. Berkowitz DB, Charette BD, Karukurichi KR, McFadden JM. Tetrahedron Asymmetry 17 869-882 (2006)
  2. Pre-steady-state kinetic and structural analysis of interaction of methionine γ-lyase from Citrobacter freundii with inhibitors. Kuznetsov NA, Faleev NG, Kuznetsova AA, Morozova EA, Revtovich SV, Anufrieva NV, Nikulin AD, Fedorova OS, Demidkina TV. J Biol Chem 290 671-681 (2015)
  3. Investigation of residues Lys112, Glu136, His138, Gly247, Tyr248, and Asp249 in the active site of yeast cystathionine beta-synthase. Lodha PH, Shadnia H, Woodhouse CM, Wright JS, Aitken SM. Biochem Cell Biol 87 531-540 (2009)
  4. Molecular characterization of Mycobacterium tuberculosis cystathionine gamma synthase--apo- and holoforms. Saha B, Mukherjee S, Das AK. Int J Biol Macromol 44 385-392 (2009)
  5. Structure of the cystathionine γ-synthase MetB from Mycobacterium ulcerans. Clifton MC, Abendroth J, Edwards TE, Leibly DJ, Gillespie AK, Ferrell M, Dieterich SH, Exley I, Staker BL, Myler PJ, Van Voorhis WC, Stewart LJ. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1154-1158 (2011)
  6. Discovery and characterization of small molecule inhibitors of cystathionine gamma-synthase with in planta activity. Bloch I, Haviv H, Rapoport I, Cohen E, Shushan RSB, Dotan N, Sher I, Hacham Y, Amir R, Gal M. Plant Biotechnol J 19 1785-1797 (2021)
  7. Identification of cystathionine γ-synthase and threonine synthase from Cicer arietinum and Lens culinaris. Morneau DJ, Jaworski AF, Aitken SM. Biochem Cell Biol 91 95-101 (2013)


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