PDBsum entry 1y7v

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Hydrolase PDB id
Jmol PyMol
Protein chain
497 a.a. *
SO4 ×13
INS ×2
Waters ×286
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: X-ray structure of human acid-beta-glucosidase covalently bo conduritol b epoxide
Structure: Glucosylceramidase. Chain: a, b. Synonym: beta-glucocerebrosidase, acid beta-glucosidase, d- n-acylsphingosine glucohydrolase, alglucerase, imiglucerase engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: gba, gc. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: ovary cells
2.40Å     R-factor:   0.242     R-free:   0.280
Authors: L.Premkumar,A.R.Sawkar,S.Boldin-Adamsky,L.Toker,I.Silman,J.W A.H.Futerman,J.L.Sussman,Israel Structural Proteomics Cente
Key ref:
L.Premkumar et al. (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. PubMed id: 15817452 DOI: 10.1074/jbc.M502799200
10-Dec-04     Release date:   12-Apr-05    
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 = INS)
matches with 91.67% similarity
Bound ligand (Het Group name = NAG)
matches with 40.74% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   6 terms 
  Biological process     metabolic process   41 terms 
  Biochemical function     protein binding     5 terms  


DOI no: 10.1074/jbc.M502799200 J Biol Chem 280:23815-23819 (2005)
PubMed id: 15817452  
X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease.
L.Premkumar, A.R.Sawkar, S.Boldin-Adamsky, L.Toker, I.Silman, J.W.Kelly, A.H.Futerman, J.L.Sussman.
Gaucher disease is an inherited metabolic disorder caused by mutations in the lysosomal enzyme acid-beta-glucosidase (GlcCerase). We recently determined the x-ray structure of GlcCerase to 2.0 A resolution (Dvir, H., Harel, M., McCarthy, A. A., Toker, L., Silman, I., Futerman, A. H., and Sussman, J. L. (2003) EMBO Rep.4, 704-709) and have now solved the structure of Glc-Cerase conjugated with an irreversible inhibitor, conduritol-B-epoxide (CBE). The crystal structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the catalytic nucleophile. However, only one of two alternative conformations of a pair of flexible loops (residues 345-349 and 394-399) located at the entrance to the active site in native GlcCerase is observed in the GlcCerase-CBE structure, a conformation in which the active site is accessible to CBE. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. This possibility is supported by a cluster of mutations in loop 394-399 that cause Gaucher disease by reducing catalytic activity. Moreover, in silico mutational analysis demonstrates that all these mutations stabilize the conformation that limits access to the active site, thus providing a mechanistic explanation of how mutations in this loop result in Gaucher disease.
  Selected figure(s)  
Figure 2.
FIG. 2. Binding of CBE to the GlcCerase active site. a, F[o] - F[c] difference omit map (contoured to 3.2 level) of the cyclohexitol ring and of Glu340 in the active site of GlcCerase. b, active site of GlcCerase with bound cyclohexitol. The cyclohexitol ring is in cyan, and its hydroxyl groups are in red. The catalytic nucleophile (Glu340 (E340)), the proposed acid/base catalyst (Glu235 (E235)), and the residues in proximity to CBE are displayed in CPK colors.
Figure 6.
FIG. 6. Surface of GlcCerase illustrating the open and closed conformations. a, the open conformation in which CBE is bound to the active site. b, the closed conformation in which the surface lid restricts access to the active site. Color coding is the same as described for Fig. 5.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 23815-23819) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
20668714 O.Goker-Alpan (2010).
Optimal therapy in Gaucher disease.
  Ther Clin Risk Manag, 6, 315-323.  
20505772 Y.H.Xu, Y.Sun, S.Barnes, and G.A.Grabowski (2010).
Comparative therapeutic effects of velaglucerase alfa and imiglucerase in a Gaucher disease mouse model.
  PLoS One, 5, e10750.  
18953653 A.Kumar, N.K.Singhal, B.Ramanujam, A.Mitra, N.R.Rameshwaram, S.K.Nadimpalli, and C.P.Rao (2009).
C(1)-/C(2)-aromatic-imino-glyco-conjugates: experimental and computational studies of binding, inhibition and docking aspects towards glycosidases isolated from soybean and jack bean.
  Glycoconj J, 26, 495-510.  
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.  
19578116 G.H.Maegawa, M.B.Tropak, J.D.Buttner, B.A.Rigat, M.Fuller, D.Pandit, L.Tang, G.J.Kornhaber, Y.Hamuro, J.T.Clarke, and D.J.Mahuran (2009).
Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease.
  J Biol Chem, 284, 23502-23516.  
19279008 K.Kitatani, K.Sheldon, V.Anelli, R.W.Jenkins, Y.Sun, G.A.Grabowski, L.M.Obeid, and Y.A.Hannun (2009).
Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid.
  J Biol Chem, 284, 12979-12988.  
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
19193629 T.Farfel-Becker, E.Vitner, H.Dekel, N.Leshem, I.B.Enquist, S.Karlsson, and A.H.Futerman (2009).
No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease.
  Hum Mol Genet, 18, 1482-1488.  
19075603 D.J.Urban, W.Zheng, O.Goker-Alpan, A.Jadhav, M.E.Lamarca, J.Inglese, E.Sidransky, and C.P.Austin (2008).
Optimization and validation of two miniaturized glucocerebrosidase enzyme assays for high throughput screening.
  Comb Chem High Throughput Screen, 11, 817-824.  
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.  
18346921 Y.H.Xu, R.Reboulet, B.Quinn, J.Huelsken, D.Witte, and G.A.Grabowski (2008).
Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid beta-glucosidase residual activity levels.
  Mol Genet Metab, 94, 190-203.  
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
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.  
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
17309337 T.D.Butters (2007).
Pharmacotherapeutic strategies using small molecules for the treatment of glycolipid lysosomal storage disorders.
  Expert Opin Pharmacother, 8, 427-435.  
17644022 T.D.Butters (2007).
Gaucher disease.
  Curr Opin Chem Biol, 11, 412-418.  
17252125 T.M.Gloster, R.Madsen, and G.J.Davies (2007).
Structural basis for cyclophellitol inhibition of a beta-glucosidase.
  Org Biomol Chem, 5, 444-446.
PDB code: 2jal
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
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
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.  
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.