A new, simple, high-affinity glycosidase inhibitor: Analysis of binding through X-ray crystallography, mutagenesis, and kinetic analysis [9]

Journal of the American Chemical Society

Volumn 122, Issue 17, 2000, Pages 4229-4230

  Williams, Spencer J ^a   Notenboom, Valerie ^a   Wicki, Jacqueline ^a   Rose, David R ^a   Withers, Stephen G ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOSIDASE; GLYCOSIDASE INHIBITOR;

BINDING KINETICS; ENZYME CONFORMATION; ENZYME INHIBITION; LETTER; MUTAGENESIS; X RAY CRYSTALLOGRAPHY;

EID: 0034600322     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja0002870     Document Type: Letter

References (25)

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17. i value.
18. i values for glyconolactams have been observed in many cases, the values observed have been similar to those of the corresponding deoxynojirimycin. In this case the lactam 1 binds more than 10-fold more tightly than the xylobiose-derived deoxynojirimycin 4. See ref 16.
19. 12 with cell dimensions a = b = 86.99 Å and c = 80.36 Å and α = β = γ = 90°. The structure was refined using wild-type Cex as a starting model (PDB code 2EXO) with CNS. (b) Brünger, A. T; Adams, P. D.; Clore, G. M.; DeLano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Acta Crystallogr. 1998, D54, 905-921; to an R-factor of 20.9% (R- free 25.0%). In order not to bias ligand geometry, dihedral angles were left unimposed. The rmsd for the Cα backbone atoms between this complex and that of native Cex was 0.315 Å.
20. 12 with cell dimensions a = b = 86.99 Å and c = 80.36 Å and α = β = γ = 90°. The structure was refined using wild-type Cex as a starting model (PDB code 2EXO) with CNS. (b) Brünger, A. T; Adams, P. D.; Clore, G. M.; DeLano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Acta Crystallogr. 1998, D54, 905-921; to an R-factor of 20.9% (R-free 25.0%). In order not to bias ligand geometry, dihedral angles were left unimposed. The rmsd for the Cα backbone atoms between this complex and that of native Cex was 0.315 Å.
21. The torsional angles measured about the C6-N1-C2-C3 and C6-N1-C2-O2 systems of 1 were 21° and 175°, respectively.
22. 4 conformation, Williams, S. J. and Withers, S. G. Unpublished data.
23. Notenboom, V.; Birsan, C.; Warren, R. A. J.; Withers, S. G.; Rose, D. R. Biochemistry 1998, 37, 4751-4758.
24. The X-ray structure of the N126A Cex mutant is essentially identical to that of the wild-type other than a slight movement of Trp84. This residue, which lies behind N126 in wild-type Cex, is observed to have moved towards the void left by the Asp to Ala mutation (a 30° rotation about χ-1) and may slightly obstruct the active site.
25. -1. Sygula, A. J. Chem. Res., S 1989, 56-57.