2IUZ

Crystal structure of Aspergillus fumigatus chitinase B1 in complex with C2-dicaffeine

Summary for 2IUZ

• Entry DOI: 10.2210/pdb2iuz/pdb
• Related: 1W9P 1W9U 1W9V 2A3A 2A3B 2A3C 2A3E
• Descriptor: CHITINASE, SULFATE ION, 1,1'-ETHANE-1,2-DIYLBIS(3,7-DIMETHYL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE), ... (4 entities in total)
• Functional Keywords: hydrolase, glycosidase, (beta-alpha)8 barrel, chitinase-c2dicaffeine complex
• Biological source: ASPERGILLUS FUMIGATUS
• Total number of polymer chains: 2
• Total formula weight: 97153.10

Authors

Schuttelkopf, A.W.,Andersen, O.A.,Rao, F.V.,Allwood, M.,Lloyd, C.M.,Eggleston, I.M.,Van Aalten, D.M.F. (deposition date: 2006-06-08, release date: 2006-06-12, Last modification date: 2024-05-08)

Primary citation

Schuttelkopf, A.W.,Andersen, O.A.,Rao, F.V.,Allwood, M.,Lloyd, C.M.,Eggleston, I.M.,Van Aalten, D.M.F.
Screening-Based Discovery and Structural Dissection of a Novel Family 18 Chitinase Inhibitor
J.Biol.Chem., 281:27278-, 2006

PubMed Abstract: Family 18 chitinases play key roles in the life cycles of a variety of organisms ranging from bacteria to man. Very recently it has been shown that one of the mammalian chitinases is highly overexpressed in the asthmatic lung and contributes to the pathogenic process through recruitment of inflammatory cells. Although several potent natural product chitinase inhibitors have been identified, their chemotherapeutic potential or their use as cell biological tools is limited due to their size, complex chemistry, and limited availability. We describe a virtual screening-based approach to identification of a novel, purine-based, chitinase inhibitor. This inhibitor acts in the low micromolar (Ki=2.8+/-0.2 microM) range in a competitive mode. Dissection of the binding mode by x-ray crystallography reveals that the compound, which consists of two linked caffeine moieties, binds in the active site through extensive and not previously observed stacking interactions with conserved, solvent exposed tryptophans. Such exposed aromatics are also present in the structures of many other carbohydrate processing enzymes. The compound exhibits favorable chemical properties and is likely to be useful as a general scaffold for development of pan-family 18 chitinase inhibitors.

PubMed: 16844689
DOI: 10.1074/JBC.M604048200

Experimental method

X-RAY DIFFRACTION (1.95 Å)