C. Steegborn et al., Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novel inhibitor, J MOL BIOL, 311(4), 2001, pp. 789-801
Cystathionine gamma -synthase catalyzes the committed step of methionine bi
osynthesis. This pathway is unique to microorganisms and plants, rendering
the enzyme an attractive target for the development of antimicrobials and h
erbicides. We solved the crystal structures of complexes of cystathionine g
amma -synthase (CGS) from Nicotiana tabacum with inhibitors of different co
mpound classes. The complex with the substrate analog DL-E-function of Arg4
23 and identifies the phosphate-binding pocket of the active site. The stru
cture shows the function of Lys165 in specificity determination and suggest
s a role for the flexible side-chain of Tyr163 in catalysis. The importance
of hydrophobic interactions for binding to the active-site center is highl
ighted by the complex with 3-(phosphono-methyl)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 acti
ve-site pocket not used by the physiological substrates. The inhibitor bind
s to the carboxylate-recognition site, and its tightly bent conformation en
ables it to occupy the novel binding pocket between Arg423 and Ser388. The
described structures suggest improvements for known inhibitors and give gui
delines for the development of new lead compounds. (C) 2001 Academic Press.