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PDBsum entry 1ogs

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Hydrolase PDB id
1ogs
Jmol
Contents
Protein chain
497 a.a. *
Ligands
SO4 ×15
NAG
NAG-NAG
Waters ×938
* Residue conservation analysis

References listed in PDB file
Key reference
Title X-Ray structure of human acid-Beta-Glucosidase, The defective enzyme in gaucher disease.
Authors H.Dvir, M.Harel, A.A.Mccarthy, L.Toker, I.Silman, A.H.Futerman, J.L.Sussman.
Ref. EMBO Rep, 2003, 4, 704-709. [DOI no: 10.1038/sj.embor.embor873]
PubMed id 12792654
Abstract
Gaucher disease, the most common lysosomal storage disease, is caused by mutations in the gene that encodes acid-beta-glucosidase (GlcCerase). Type 1 is characterized by hepatosplenomegaly, and types 2 and 3 by early or chronic onset of severe neurological symptoms. No clear correlation exists between the approximately 200 GlcCerase mutations and disease severity, although homozygosity for the common mutations N370S and L444P is associated with non- neuronopathic and neuronopathic disease, respectively. We report the X-ray structure of GlcCerase at 2.0 A resolution. The catalytic domain consists of a (beta/alpha)(8) TIM barrel, as expected for a member of the glucosidase hydrolase A clan. The distance between the catalytic residues E235 and E340 is consistent with a catalytic mechanism of retention. N370 is located on the longest alpha-helix (helix 7), which has several other mutations of residues that point into the TIM barrel. Helix 7 is at the interface between the TIM barrel and a separate immunoglobulin-like domain on which L444 is located, suggesting an important regulatory or structural role for this non-catalytic domain. The structure provides the possibility of engineering improved GlcCerase for enzyme-replacement therapy, and for designing structure-based drugs aimed at restoring the activity of defective GlcCerase.
Figure 1.
Figure 1 Reaction catalysed by acid- -glucosidase. Acid- -glucosidase (GlcCerase) hydrolyses the -glucosyl linkage of glucosylceramide (GlcCer), to yield ceramide and glucose.
Figure 3.
Figure 3 Active site of acid- -glucosidase. (A) The catalytic and glucone-binding site of acid- -glucosidase (GlcCerase). The catalytic glutamates are shown as ball-and-stick models and amino-acid residues nearby are shown as sticks. Hydrogen bonds are shown as dashed lines for those residues close enough to contact the glutamates. These residues may be involved directly in catalysis or may modulate the protonation states of the carboxyl groups. The others residues are near the docked glucosyl moiety (see (B)), and these may thus stabilize its interaction with GlcCerase. (B) Three-dimensional surface diagram of GlcCerase (created using PyMOL (http://www.pymol.org)), with a model of the docked substrate (based on the coordinates of galactosylceramide (Nyholm et al., 1990) and modified for GlcCer). Hydrophobic residues (W, F, Y, L, I, V, M and C; Hopp & Woods, 1981) are shown in blue, and the active-site residues (E235 and E340) in yellow. GlcCer is shown in CPK format (carbon atoms in green, and oxygen atoms in red).
The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO Rep (2003, 4, 704-709) copyright 2003.
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