Crystal structure of β-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone.
β-Hexosaminidases (β-hex) are a group of glycosyl hydrolase isozymes that break down neutral and sialylated glycosphingolipids in the lysosomes, thereby preventing their buildup in neuronal cells. Some mutants of β-hex have decreased folding stability that results in adult-onset forms of lysosomal storage diseases. However, prevention of the harmful accumulation of glycolipids only requires 10% of wild-type activity. Pyrimethamine (PYR) is a potential pharmacological chaperone that works by stabilizing these mutant enzymes sufficiently to allow more β-hex to arrive in the lysosome, where it can carry out its function. An X-ray structure of the complex between human β-hexosaminidase B (HexB) and PYR has been determined to 2.8 Å. PYR binds to the active site of HexB where several favorable van der Waals contacts and hydrogen bonds are introduced. Small adjustments of the enzyme structure are required to accommodate the ligand, and details of the inhibition and stabilization properties of PYR are discussed.
Department of Biochemistry, 4-29 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Katherine S
KS
Bateman
Maia M
MM
Cherney
Don J
DJ
Mahuran
Michael
M
Tropak
Michael N G
MN
James
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry; D011739:Pyrimethamine / Q000737:chemistry*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry*
D007527:Isoenzymes; D021122:Protein Subunits; D001619:beta-N-Acetylhexosaminidases; D011739:Pyrimethamine
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13046-51
16135570
J Biol Chem. 2001 Mar 30;276(13):10330-7
11124970
Chem Biol. 2007 Feb;14(2):153-64
17317569
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
20383002
J Biol Chem. 2007 Mar 23;282(12):9150-61
17237499
Hum Genet. 1992 Mar;88(5):513-23
1348043
J Mol Biol. 2003 May 2;328(3):669-81
12706724
FEBS J. 2007 Oct;274(19):4951-61
17894780
J Appl Crystallogr. 2002 Dec;35(6):720-726
24899734
J Am Chem Soc. 2007 Mar 28;129(12):3634-40
17335207
J Struct Biol. 1999 Apr-May;125(2-3):156-65
10222271
J Mol Biol. 2006 Jun 16;359(4):913-29
16698036
Glycobiology. 2010 Mar;20(3):356-65
19917668
J Biol Chem. 2002 Jan 25;277(4):2562-72
11707436
Can J Biochem. 1980 Apr;58(4):287-94
7378875
Biochim Biophys Acta. 1999 Oct 8;1455(2-3):105-38
10571007
Biochemistry. 1988 Jul 12;27(14):5216-26
2971395
Proc Natl Acad Sci U S A. 1978 Jul;75(7):3327-31
28524
Science. 2002 Apr 19;296(5567):545-7
11964483
J Mol Biol. 2003 Apr 11;327(5):1093-109
12662933
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Methods Enzymol. 1997;276:307-26
27754618
J Synchrotron Radiat. 2002 Nov 1;9(Pt 6):401-6
12409628
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2997-3002
9501204
J Biol Chem. 1981 Dec 25;256(24):12926-32
6458607
Mol Genet Metab. 2011 Jan;102(1):6-12
20926324
J Biol Chem. 2004 Apr 2;279(14):13478-87
14724290
Acta Crystallogr D Biol Crystallogr. 1998 Nov 1;54(Pt 6 Pt 2):1285-94
10089505
Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
2025413
Nature. 1992 Jan 30;355(6359):472-5
18481394
Glycobiology. 2001 Jul;11(7):549-56
11447134