Fig. 3 A. Observed electron density (2Fobs 2 Fcalc at 1s) for the PUGNAc–imidazole hybrid (4) bound to BtGH84. Residues of the protein are shown in
green with the positions of the equivalent side-chains from the native enzyme structure in purple. B. An overlay of the BtGH84 PUGNAc–imidazole
hybrid complex with the CpGH84H (PUGNAc moiety only shown in yellow) PUGNAc complex. This figure was drawn using BOBSCRIPT.19
which instead forms a hydrogen bond with the catalytic acid,
Asp398, of that enzyme.9
Engineering Research Council of Canada, and the
Biotechnology and Biochemical Sciences Research Council for
funding.
These observations provide insight into the relative KI values
determined for PUGNAc–imidazole and gluco-nagstatin with
O-GlcNAcase. The differences in KI values between LOGNAc and
PUGNAc likely stem from the presence of the N-phenyl
carbamoyl group. The PUGNAc–imidazole hybrid, which has a
similar KI value to LOGNAc, is bound with the phenyl group
oriented differently such that it does not efficiently capture
available binding energy. Interestingly, gluco-nagstatin is a 40-fold
poorer inhibitor toward the family 84 human O-GlcNAcase as
compared to the family 20 b-hexosaminidase. The structural basis
for this difference in affinities is difficult to account for but may
arise from differences in the acidity of the enzymic general catalytic
acid. gluco-Nagstatin binds 3-fold better than LOGNAc itself and
so the tetrahydroimidazopyridine scaffold offers an equally potent,
yet stable, scaffold on which to graft substituents conferring
improved potency when the constraints of decreased flexibility are
overcome.
Notes and references
{ For the family classification of glycoside hydrolases see URL: http://
afmb.cnrs-mrs.fr/CAZY/.20
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Keith Stubbs and Bruno Bernet are thanked for expert
assistance. DJV is a scholar of the MSFHR and a Canada
Research Chair in Chemical Glycobiology. We thank the Swiss
National Science Foundation, the Natural Sciences and
4374 | Chem. Commun., 2006, 4372–4374
This journal is ß The Royal Society of Chemistry 2006