PDBsum entry 1ogs

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Hydrolase PDB id
Protein chain
497 a.a. *
SO4 ×15
Waters ×938
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human acid-beta-glucosidase
Structure: Glucosylceramidase. Chain: a, b. Synonym: glucocerebrosidase, beta-glucocerebrosidase, acid beta-glucosidase, d-glucosyl-n-acylsphingosine glucohydrolase, alglucerase, imiglucerase. Engineered: yes
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho
2.00Å     R-factor:   0.195     R-free:   0.230
Authors: H.Dvir,M.Harel,A.A.Mccarthy,L.Toker,I.Silman,A.H.Futerman, J.L.Sussman
Key ref:
H.Dvir et al. (2003). X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep, 4, 704-709. PubMed id: 12792654 DOI: 10.1038/sj.embor.embor873
13-May-03     Release date:   03-Jul-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P04062  (GLCM_HUMAN) -  Glucosylceramidase
536 a.a.
497 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Glucosylceramidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: D-glucosyl-N-acylsphingosine + H2O = D-glucose + N-acylsphingosine
+ H(2)O
Bound ligand (Het Group name = NAG)
matches with 62.50% similarity
+ N-acylsphingosine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   5 terms 
  Biological process     metabolic process   23 terms 
  Biochemical function     protein binding     5 terms  


DOI no: 10.1038/sj.embor.embor873 EMBO Rep 4:704-709 (2003)
PubMed id: 12792654  
X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease.
H.Dvir, M.Harel, A.A.McCarthy, L.Toker, I.Silman, A.H.Futerman, J.L.Sussman.
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.
  Selected figure(s)  
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 (, 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.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21457079 J.M.Benito, J.M.García Fernández, and C.O.Mellet (2011).
Pharmacological chaperone therapy for Gaucher disease: a patent review.
  Expert Opin Ther Pat, 21, 885-903.  
21286689 M.Shanmuganathan, and P.Britz-McKibbin (2011).
Inhibitor screening of pharmacological chaperones for lysosomal β-glucocerebrosidase by capillary electrophoresis.
  Anal Bioanal Chem, 399, 2843-2853.  
19741058 B.Brumshtein, P.Salinas, B.Peterson, V.Chan, I.Silman, J.L.Sussman, P.J.Savickas, G.S.Robinson, and A.H.Futerman (2010).
Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages.
  Glycobiology, 20, 24-32.
PDB code: 2wkl
20945356 C.E.Bobst, J.J.Thomas, P.A.Salinas, P.Savickas, and I.A.Kaltashov (2010).
Impact of oxidation on protein therapeutics: conformational dynamics of intact and oxidized acid-β-glucocerebrosidase at near-physiological pH.
  Protein Sci, 19, 2366-2378.  
20534487 C.P.Phenix, B.P.Rempel, K.Colobong, D.J.Doudet, M.J.Adam, L.A.Clarke, and S.G.Withers (2010).
Imaging of enzyme replacement therapy using PET.
  Proc Natl Acad Sci U S A, 107, 10842-10847.  
21221911 D.A.Hughes, and G.M.Pastores (2010).
The pathophysiology of GD - current understanding and rationale for existing and emerging therapeutic approaches.
  Wien Med Wochenschr, 160, 594-599.  
21098288 J.Lu, J.Chiang, R.R.Iyer, E.Thompson, C.R.Kaneski, D.S.Xu, C.Yang, M.Chen, R.J.Hodes, R.R.Lonser, R.O.Brady, and Z.Zhuang (2010).
Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.
  Proc Natl Acad Sci U S A, 107, 21665-21670.  
20490603 J.R.Ketudat Cairns, and A.Esen (2010).
  Cell Mol Life Sci, 67, 3389-3405.  
20668714 O.Goker-Alpan (2010).
Optimal therapy in Gaucher disease.
  Ther Clin Risk Manag, 6, 315-323.  
20148966 R.Khanna, E.R.Benjamin, L.Pellegrino, A.Schilling, B.A.Rigat, R.Soska, H.Nafar, B.E.Ranes, J.Feng, Y.Lun, A.C.Powe, D.J.Palling, B.A.Wustman, R.Schiffmann, D.J.Mahuran, D.J.Lockhart, and K.J.Valenzano (2010).
The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase.
  FEBS J, 277, 1618-1638.  
19437524 B.Brumshtein, M.Aguilar-Moncayo, M.I.García-Moreno, C.Ortiz Mellet, J.M.García Fernández, I.Silman, Y.Shaaltiel, D.Aviezer, J.L.Sussman, and A.H.Futerman (2009).
6-Amino-6-deoxy-5,6-di-N-(N'-octyliminomethylidene)nojirimycin: synthesis, biological evaluation, and crystal structure in complex with acid beta-glucosidase.
  Chembiochem, 10, 1480-1485.
PDB code: 2wcg
19217815 B.Liou, and G.A.Grabowski (2009).
Participation of asparagine 370 and glutamine 235 in the catalysis by acid beta-glucosidase: the enzyme deficient in Gaucher disease.
  Mol Genet Metab, 97, 65-74.  
19459886 J.Vithayathil, G.Gibney, A.D.Baxevanis, B.K.Stubblefield, E.Sidransky, and N.Tayebi (2009).
Glucocerebrosidase mutation H255Q appears to be exclusively in cis with D409H: structural implications.
  Clin Genet, 75, 503-504.  
19672277 P.Saftig, and J.Klumperman (2009).
Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function.
  Nat Rev Mol Cell Biol, 10, 623-635.  
19374450 R.L.Lieberman, J.A.D'aquino, D.Ringe, and G.A.Petsko (2009).
Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability.
  Biochemistry, 48, 4816-4827.
PDB codes: 3gxd 3gxf 3gxi 3gxm 3gxn 3gxp 3gxt
19790257 T.S.Kang, and R.C.Stevens (2009).
Structural aspects of therapeutic enzymes to treat metabolic disorders.
  Hum Mutat, 30, 1591-1610.  
19717598 Y.G.Kim, J.H.Kim, and K.J.Kim (2009).
Crystal structure of the Salmonella enterica serovar typhimurium virulence factor SrfJ, a glycoside hydrolase family enzyme.
  J Bacteriol, 191, 6550-6554.
PDB code: 2wnw
19830760 Z.Luan, K.Higaki, M.Aguilar-Moncayo, H.Ninomiya, K.Ohno, M.I.García-Moreno, C.Ortiz Mellet, J.M.García Fernández, and Y.Suzuki (2009).
Chaperone activity of bicyclic nojirimycin analogues for Gaucher mutations in comparison with N-(n-nonyl)deoxynojirimycin.
  Chembiochem, 10, 2780-2792.  
18070135 A.Zay, F.Y.Choy, P.Macleod, and C.R.Tan-Dy (2008).
Perinatal lethal Gaucher's disease without prenatal complications.
  Clin Genet, 73, 191-195.  
19461852 B.Brumshtein, H.M.Greenblatt, A.H.Futerman, I.Silman, and J.L.Sussman (2008).
Control of the rate of evaporation in protein crystallization by the 'microbatch under oil' method.
  J Appl Crystallogr, 41, 969-971.  
18338393 K.S.Hruska, M.E.LaMarca, C.R.Scott, and E.Sidransky (2008).
Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA).
  Hum Mutat, 29, 567-583.  
17803231 S.Atrian, E.López-Viñas, P.Gómez-Puertas, A.Chabás, L.Vilageliu, and D.Grinberg (2008).
An evolutionary and structure-based docking model for glucocerebrosidase-saposin C and glucocerebrosidase-substrate interactions - relevance for Gaucher disease.
  Proteins, 70, 882-891.  
18783340 Y.Kacher, B.Brumshtein, S.Boldin-Adamsky, L.Toker, A.Shainskaya, I.Silman, J.L.Sussman, and A.H.Futerman (2008).
Acid beta-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy.
  Biol Chem, 389, 1361-1369.
PDB code: 2vt0
17666401 B.Brumshtein, H.M.Greenblatt, T.D.Butters, Y.Shaaltiel, D.Aviezer, I.Silman, A.H.Futerman, and J.L.Sussman (2007).
Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease.
  J Biol Chem, 282, 29052-29058.
PDB codes: 2v3d 2v3e
17921497 C.Deutsch, and B.Krishnamoorthy (2007).
Four-body scoring function for mutagenesis.
  Bioinformatics, 23, 3009-3015.  
17713797 I.Z.Zubrzycki, A.Borcz, M.Wiacek, and W.Hagner (2007).
The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-beta-glucosidase.
  J Mol Model, 13, 1133-1139.  
17954913 J.R.Alattia, J.E.Shaw, C.M.Yip, and G.G.Privé (2007).
Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C.
  Proc Natl Acad Sci U S A, 104, 17394-17399.  
17884629 J.W.Kozarich (2007).
New LSD therapies unfolding.
  Chem Biol, 14, 976-977.  
17329247 M.E.Caines, M.D.Vaughan, C.A.Tarling, S.M.Hancock, R.A.Warren, S.G.Withers, and N.C.Strynadka (2007).
Structural and mechanistic analyses of endo-glycoceramidase II, a membrane-associated family 5 glycosidase in the Apo and GM3 ganglioside-bound forms.
  J Biol Chem, 282, 14300-14308.
PDB codes: 2osw 2osx 2osy
17187079 R.L.Lieberman, B.A.Wustman, P.Huertas, A.C.Powe, C.W.Pine, R.Khanna, M.G.Schlossmacher, D.Ringe, and G.A.Petsko (2007).
Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.
  Nat Chem Biol, 3, 101-107.
PDB codes: 2nsx 2nt0 2nt1
17644022 T.D.Butters (2007).
Gaucher disease.
  Curr Opin Chem Biol, 11, 412-418.  
17905739 Y.Kitago, S.Karita, N.Watanabe, M.Kamiya, T.Aizawa, K.Sakka, and I.Tanaka (2007).
Crystal structure of Cel44A, a glycoside hydrolase family 44 endoglucanase from Clostridium thermocellum.
  J Biol Chem, 282, 35703-35711.
PDB codes: 2e0p 2e4t 2eex 2ej1 2eo7 2eqd
17524049 Y.Shaaltiel, D.Bartfeld, S.Hashmueli, G.Baum, E.Brill-Almon, G.Galili, O.Dym, S.A.Boldin-Adamsky, I.Silman, J.L.Sussman, A.H.Futerman, and D.Aviezer (2007).
Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system.
  Plant Biotechnol J, 5, 579-590.
PDB code: 2v3f
17894779 Z.Yu, A.R.Sawkar, and J.W.Kelly (2007).
Pharmacologic chaperoning as a strategy to treat Gaucher disease.
  FEBS J, 274, 4944-4950.  
17201413 Z.Yu, A.R.Sawkar, L.J.Whalen, C.H.Wong, and J.W.Kelly (2007).
Isofagomine- and 2,5-anhydro-2,5-imino-D-glucitol-based glucocerebrosidase pharmacological chaperones for Gaucher disease intervention.
  J Med Chem, 50, 94.  
17139081 B.Brumshtein, M.R.Wormald, I.Silman, A.H.Futerman, and J.L.Sussman (2006).
Structural comparison of differently glycosylated forms of acid-beta-glucosidase, the defective enzyme in Gaucher disease.
  Acta Crystallogr D Biol Crystallogr, 62, 1458-1465.
PDB code: 2j25
16293621 B.Liou, A.Kazimierczuk, M.Zhang, C.R.Scott, R.S.Hegde, and G.A.Grabowski (2006).
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.
  J Biol Chem, 281, 4242-4253.
PDB code: 2f61
16934036 H.H.Chang, N.Asano, S.Ishii, Y.Ichikawa, and J.Q.Fan (2006).
Hydrophilic iminosugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients.
  FEBS J, 273, 4082-4092.  
17001097 L.Banci, I.Bertini, S.Cusack, Jong, U.Heinemann, E.Y.Jones, F.Kozielski, K.Maskos, A.Messerschmidt, R.Owens, A.Perrakis, A.Poterszman, G.Schneider, C.Siebold, I.Silman, T.Sixma, G.Stewart-Jones, J.L.Sussman, J.C.Thierry, and D.Moras (2006).
First steps towards effective methods in exploiting high-throughput technologies for the determination of human protein structures of high biomedical value.
  Acta Crystallogr D Biol Crystallogr, 62, 1208-1217.  
16261622 M.J.Eblan, J.Nguyen, S.G.Ziegler, A.Lwin, M.Hanson, M.Gallardo, R.Weiser, M.De Lucca, A.Singleton, and E.Sidransky (2006).
Glucocerebrosidase mutations are also found in subjects with early-onset parkinsonism from Venezuela.
  Mov Disord, 21, 282-283.  
16298303 A.R.Sawkar, S.L.Adamski-Werner, W.C.Cheng, C.H.Wong, E.Beutler, K.P.Zimmer, and J.W.Kelly (2005).
Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles.
  Chem Biol, 12, 1235-1244.  
15585273 C.C.Barrias, M.A.Martins, M.A.Sá Miranda, and M.A.Barbosa (2005).
Adsorption of a therapeutic enzyme to self-assembled monolayers: effect of surface chemistry and solution pH on the amount and activity of adsorbed enzyme.
  Biomaterials, 26, 2695-2704.  
16086325 L.Kowarz, O.Goker-Alpan, S.Banerjee-Basu, M.E.LaMarca, L.Kinlaw, R.Schiffmann, A.D.Baxevanis, and E.Sidransky (2005).
Gaucher mutation N188S is associated with myoclonic epilepsy.
  Hum Mutat, 26, 271.  
15817452 L.Premkumar, A.R.Sawkar, S.Boldin-Adamsky, L.Toker, I.Silman, J.W.Kelly, A.H.Futerman, and J.L.Sussman (2005).
X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease.
  J Biol Chem, 280, 23815-23819.
PDB code: 1y7v
15785807 M.Egido-Gabás, P.Serrano, J.Casas, A.Llebaria, and A.Delgado (2005).
New aminocyclitols as modulators of glucosylceramide metabolism.
  Org Biomol Chem, 3, 1195-1201.  
15813845 M.Jmoudiak, and A.H.Futerman (2005).
Gaucher disease: pathological mechanisms and modern management.
  Br J Haematol, 129, 178-188.  
15982918 M.Schmitz, M.Alfalah, J.M.Aerts, H.Y.Naim, and K.P.Zimmer (2005).
Impaired trafficking of mutants of lysosomal glucocerebrosidase in Gaucher's disease.
  Int J Biochem Cell Biol, 37, 2310-2320.  
16204888 S.Albeck, Y.Burstein, O.Dym, Y.Jacobovitch, N.Levi, R.Meged, Y.Michael, Y.Peleg, J.Prilusky, G.Schreiber, I.Silman, T.Unger, and J.L.Sussman (2005).
Three-dimensional structure determination of proteins related to human health in their functional context at The Israel Structural Proteomics Center (ISPC). This paper was presented at ICCBM10.
  Acta Crystallogr D Biol Crystallogr, 61, 1364-1372.  
16231389 X.Zhu, K.A.Sheth, S.Li, H.H.Chang, and J.Q.Fan (2005).
Rational design and synthesis of highly potent beta-glucocerebrosidase inhibitors.
  Angew Chem Int Ed Engl, 44, 7450-7453.  
15232573 A.H.Futerman, and G.van Meer (2004).
The cell biology of lysosomal storage disorders.
  Nat Rev Mol Cell Biol, 5, 554-565.  
15019270 A.H.Futerman, J.L.Sussman, M.Horowitz, I.Silman, and A.Zimran (2004).
New directions in the treatment of Gaucher disease.
  Trends Pharmacol Sci, 25, 147-151.  
15146461 M.Montfort, A.Chabás, L.Vilageliu, and D.Grinberg (2004).
Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms.
  Hum Mutat, 23, 567-575.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.