TY - JOUR
T1 - Structure of saccharomyces cerevisiae chitinase 1 and screening-based discovery of potent inhibitors
AU - Hurtado-Guerrero, Ramon
AU - van Aalten, Daan M. F.
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2007/5/29
Y1 - 2007/5/29
N2 - Chitinases hydrolyse the ß(1,4)-glycosidic bonds of chitin, an essential fungal cell wall component. Genetic data on a subclass of fungal family 18 chitinases have suggested a role in cell wall morphology. Specific inhibitors of these enzymes would be useful as tools to study their role in cell wall morphogenesis and could possess antifungal properties. Here, we describe the crystallographic structure of a fungal “plant-type” family 18 chitinase, that of Saccharomyces cerevisiae CTS1. The enzyme is active against 4-methylumbelliferyl chitooligosaccharides and displays an unusually low pH optimum for activity. A library screen against ScCTS1 yielded hits with Ki's as low as 3.2 µM. Crystal structures of ScCTS1 in complex with inhibitors from three series reveal striking mimicry of carbohydrate substrate by small aromatic moieties and a pocket that could be further exploited in optimization of these inhibitors.
AB - Chitinases hydrolyse the ß(1,4)-glycosidic bonds of chitin, an essential fungal cell wall component. Genetic data on a subclass of fungal family 18 chitinases have suggested a role in cell wall morphology. Specific inhibitors of these enzymes would be useful as tools to study their role in cell wall morphogenesis and could possess antifungal properties. Here, we describe the crystallographic structure of a fungal “plant-type” family 18 chitinase, that of Saccharomyces cerevisiae CTS1. The enzyme is active against 4-methylumbelliferyl chitooligosaccharides and displays an unusually low pH optimum for activity. A library screen against ScCTS1 yielded hits with Ki's as low as 3.2 µM. Crystal structures of ScCTS1 in complex with inhibitors from three series reveal striking mimicry of carbohydrate substrate by small aromatic moieties and a pocket that could be further exploited in optimization of these inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=34248596802&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2007.03.015
DO - 10.1016/j.chembiol.2007.03.015
M3 - Article
AN - SCOPUS:34248596802
SN - 1074-5521
VL - 14
SP - 589
EP - 599
JO - Chemistry & Biology
JF - Chemistry & Biology
IS - 5
ER -