PDBsum entry 2nsx

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Hydrolase PDB id
Protein chain
497 a.a.
NDG ×2
SO4 ×18
GOL ×2
NAG ×3
IFM ×2
Waters ×1006

References listed in PDB file
Key reference
Title Structure of acid beta-Glucosidase with pharmacological chaperone provides insight into gaucher disease.
Authors R.L.Lieberman, B.A.Wustman, P.Huertas, A.C.Powe, C.W.Pine, R.Khanna, M.G.Schlossmacher, D.Ringe, G.A.Petsko.
Ref. Nat Chem Biol, 2007, 3, 101-107. [DOI no: 10.1038/nchembio850]
PubMed id 17187079
Gaucher disease results from mutations in the lysosomal enzyme acid beta-glucosidase (GCase). Although enzyme replacement therapy has improved the health of some affected individuals, such as those with the prevalent N370S mutation, oral treatment with pharmacological chaperones may be therapeutic in a wider range of tissue compartments by restoring sufficient activity of endogenous mutant GCase. Here we demonstrate that isofagomine (IFG, 1) binds to the GCase active site, and both increases GCase activity in cell lysates and restores lysosomal trafficking in cells containing N370S mutant GCase. We also compare the crystal structures of IFG-bound GCase at low pH with those of glycerol-bound GCase at low pH and apo-GCase at neutral pH. Our data indicate that IFG induces active GCase, which is secured by interactions with Asn370. The design of small molecules that stabilize substrate-bound conformations of mutant proteins may be a general therapeutic strategy for diseases caused by protein misfolding and mistrafficking.
Figure 3.
(a) Ball-and-stick representation of glycerol-bound acidic active site. (b) Ball-and-stick representation of active site seen in inh-like conformation in neutral. (c) Ball-and-stick representation of active site seen in acidic-like conformation in neutral. (d) Ball-and-stick representation of IFG-bound inh active site. Difference (F[o] - F[c]) electron density (green) is contoured at 3 and was calculated using only respective GCase coordinates. Asn396 and Trp381 are omitted for clarity. Hydrogen bonding interactions to ordered water molecules are indicated by gray dashed lines. (e) Schematic diagram of hydrogen bonding interactions involved in stabilizing IFG in the active site of GCase. Distances are in Å.
Figure 5.
(a,b) Conformation with IFG bound (a) and glycerol (GOL) bound (b). Residues in dark orange derive from PDB code 1OGS; those in yellow are acidic.
The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2007, 3, 101-107) copyright 2007.
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