Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins.
Chitin hydrolases have been identified in a variety of organisms ranging from bacteria to eukaryotes. They have been proposed to be possible targets for the design of novel chemotherapeutics against human pathogens such as fungi and protozoan parasites as mammals were not thought to possess chitin-processing enzymes. Recently, a human chitotriosidase was described as a marker for Gaucher disease with plasma levels of the enzyme elevated up to 2 orders of magnitude. The chitotriosidase was shown to be active against colloidal chitin and is inhibited by the family 18 chitinase inhibitor allosamidin. Here, the crystal structure of the human chitotriosidase and complexes with a chitooligosaccharide and allosamidin are described. The structures reveal an elongated active site cleft, compatible with the binding of long chitin polymers, and explain the inactivation of the enzyme through an inherited genetic deficiency. Comparison with YM1 and HCgp-39 shows how the chitinase has evolved into these mammalian lectins by the mutation of key residues in the active site, tuning the substrate binding specificity. The soaking experiments with allosamidin and chitooligosaccharides give insight into ligand binding properties and allow the evaluation of differential binding and design of species-selective chitinase inhibitors.
Fusetti
Fabrizia
F
Laboratory of Biophysical Chemistry, University of Groningen, The Netherlands.
von Moeller
Holger
H
Houston
Douglas
D
Rozeboom
Henriette J
HJ
Dijkstra
Bauke W
BW
Boot
Rolf G
RG
Aerts
Johannes M F G
JM
van Aalten
Daan M F
DM
D000595:Amino Acid Sequence; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006596:Hexosaminidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D037102:Lectins; D006596:Hexosaminidases; C086400:chitotriosidase